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WO2014144685A2 - Methods for identifying arthropod repellents and attractants, and compounds and compositions identified by such methods - Google Patents

Methods for identifying arthropod repellents and attractants, and compounds and compositions identified by such methods Download PDF

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Publication number
WO2014144685A2
WO2014144685A2 PCT/US2014/029201 US2014029201W WO2014144685A2 WO 2014144685 A2 WO2014144685 A2 WO 2014144685A2 US 2014029201 W US2014029201 W US 2014029201W WO 2014144685 A2 WO2014144685 A2 WO 2014144685A2
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WO
WIPO (PCT)
Prior art keywords
compounds
optionally substituted
neuron
group
arthropod
Prior art date
Application number
PCT/US2014/029201
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French (fr)
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WO2014144685A3 (en
Inventor
Anandasankar Ray
Sean Michael BOYLE
Dyan MACWILLIAM
Genevieve Mitchell TAUXE
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The Regents Of The University Of California
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Application filed by The Regents Of The University Of California filed Critical The Regents Of The University Of California
Priority to BR112015023640A priority Critical patent/BR112015023640A2/en
Priority to EP14765711.8A priority patent/EP2972299A4/en
Priority to EP17184047.3A priority patent/EP3409115A3/en
Publication of WO2014144685A2 publication Critical patent/WO2014144685A2/en
Publication of WO2014144685A3 publication Critical patent/WO2014144685A3/en
Priority to US14/855,024 priority patent/US20160003805A1/en
Priority to US15/494,401 priority patent/US9897592B2/en
Priority to US15/851,130 priority patent/US10768168B2/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5058—Neurological cells
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A01N31/02—Acyclic compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A01N31/06—Oxygen or sulfur directly attached to a cycloaliphatic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/02—Amines; Quaternary ammonium compounds
    • A01N33/04—Nitrogen directly attached to aliphatic or cycloaliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N35/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical
    • A01N35/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical containing aliphatically bound aldehyde or keto groups, or thio analogues thereof; Derivatives thereof, e.g. acetals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N35/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical
    • A01N35/06—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical containing keto or thioketo groups as part of a ring, e.g. cyclohexanone, quinone; Derivatives thereof, e.g. ketals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N35/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical
    • A01N35/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical at least one of the bonds to hetero atoms is to nitrogen
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/02—Saturated carboxylic acids or thio analogues thereof; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing within the same carbon skeleton a carboxylic group or a thio analogue, or a derivative thereof, and a carbon atom having only two bonds to hetero atoms with at the most one bond to halogen, e.g. keto-carboxylic acids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N41/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom
    • A01N41/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom containing a sulfur-to-oxygen double bond
    • A01N41/10—Sulfones; Sulfoxides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
    • A01N43/08—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
    • A01N43/10—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with sulfur as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G01N33/5032—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects on intercellular interactions

Definitions

  • the present disclosure relates generally to the field of arthropod repellents and attractants, and more specifically to methods of identifying such repellents based on affecting the detection of human skin odors in arthropods.
  • Blood-feeding insects such as mosquitoes
  • pathogens like malaria parasites, dengue viruses, and filarial worms to hundreds of millions of people every year.
  • Insect repellents can be very effective in reducing vectorial capacity by
  • DEET N,N-Diethyl-m-toluamide
  • DEET is a solvent capable
  • repellent for at least one arthropod species by a) providing a candidate compound and a skin odor; b) providing a sample that includes a neuron, wherein the neuron
  • the candidate compound by determining whether or not the candidate compound masks or inhibits the detection of the skin odor by the neuron.
  • the neuron expresses at least one of AgGr22,
  • AgGr23, and AgGr24 in Anopheles gambiae also called Grl, Gr2 and Gr3
  • the skin odor is an individual odorant or the skin odor comprises a plurality of odorants.
  • the neuron is a cpA neuron in maxillary palps of mosquitoes. In certain embodiments, the neuron is from an arthropod. In certain embodiments, the neuron is from an insect.
  • arthropod species is identified by determining whether or not the candidate compound masks or inhibits at least 75% of the detection of the skin odor by the neuron.
  • the compound is identified in an in vitro assay or in vivo assay.
  • the activity of the neuron is measured by one or more
  • electrophysiological parameters one or more activity imaging parameters, or any combination thereof
  • composition that includes one or more compound identified according to any of the methods described above.
  • a system that includes: a) a sample comprising a neuron, wherein the neuron expresses at least
  • arthropod species wherein the one or more compounds each masks or inhibits the
  • the skin odor is an individual odorant or the skin
  • the neuron is a cpA
  • the neuron is from an arthropod. In certain embodiments, the neuron is from an arthropod.
  • the neuron is from an insect. In some embodiments, the one or more of the compounds
  • composition for use as an arthropod repellent that
  • R 1 and R 2 are each independently selected from the group consisting H, OH,
  • R 1 and R 2 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or
  • heteroaromatic ring system having 3 to 6 ring carbon atoms
  • R 11 and R 12 are each independently selected from the group consisting of H,
  • R 11 and R 12 can be linked together to form an optionally
  • R 5 and R 6 are each independently selected from the group consisting of H, D, a halide, and optionally substituted aliphatic group;
  • R 7 is selected from the group consisting of an optionally substituted aliphatic
  • R 5 and R 6 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; or
  • R 6 and R 7 can be linked together to form an optionally substituted ring
  • cycloalkenyl selected from the group consisting of cycloalkenyl, aryl, and heterocycle, or any combinations thereof.
  • the composition includes: i) one or more
  • the one or more compounds of formula (la) are
  • the one or more alkyl 2-oxopropanoates are selected from the group consisting of ethyl 2-oxopropanoate and
  • composition for use an arthropod repellent that includes one or more compounds of formula (XII):
  • W is -NR c R d ;
  • a m is an aliphatic group
  • each A" is independently an aliphatic group
  • each R a , R b , R c and R d is independently H or an aliphatic group
  • each R n is independently H or an aliphatic group
  • x is an integer greater than or equal to 1 ;
  • x is 0 to 8. In certain embodiments, x is 1 or 2; W
  • each R a , R b , R c , R d , and R n is H; and each A" and A m is independently
  • the compound is:
  • composition for use as an arthropod repellent that includes: i) one or more pyruvate inhibitors selected from the compounds of Table A,
  • the composition is formulated into a lotion, a
  • cream cream, a spray, a dust, a vaporizer, a treated mat, a treated outerwear, an oil, a candle, or a wicked apparatus.
  • composition for use as an arthropod attractant that
  • R 1 and R 2 are each independently selected from the group consisting H, OH,
  • R 1 and R 2 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or
  • heteroaromatic ring system having 3 to 6 ring carbon atoms
  • R 26 , and R 28 -R 30 are each independently selected from the group consisting of
  • R 26 , and R 28 -R 3 J 0 U can be linked together to form one or more optionally substituted
  • cycloalkyl cycloalkenyl, cycloalkynyl, aryl, or heterocycle
  • R 26 , and R 28 -R 3 J 0 U are each independently selected from the group consisting of
  • cycloalkyl cycloalkenyl, cycloalkynyl, aryl, or heterocycle
  • R 31 -R 34 are each independently selected the group consisting of H, D, a
  • cycloalkenyl cycloalkynyl, aryl, or heterocycle, or any combination thereof.
  • composition for use as an arthropod attractant that
  • one or more compounds selected from thiophene, lH-pyrrole, hex-5-en-2-one, and methyl 2-methylpropanoate are selected from thiophene, lH-pyrrole, hex-5-en-2-one, and methyl 2-methylpropanoate.
  • composition for use as an arthropod attractant that
  • the cycloalkanone is a C 4 to C 6 cycloalkanone.
  • the cycloalkanone is cyclopentanone. In another embodiment, the cycloalkanone is cyclopentanone.
  • composition includes cyclopentanone and ethyl acetate.
  • composition for use as an arthropod attractant that
  • the composition is used in an arthropod trap. In one embodiment, the composition is used in an arthropod trap.
  • arthropod trap is suction-based, light-based, electric current-based, or any combination thereof
  • composition comprising a compound identified
  • FIG. la is schematic of the maxillary palp capitate peg sensillum with
  • FIG. lb depicts representative traces and mean change in firing rate of the
  • Aedes aegypti cpA (large amplitude that expresses Grl, Gr2 and Gr3) neuron to a
  • FIG. lc includes a bar graph (left) summarizing the cpA response for
  • traces and mean increase in firing rate of the cpA neuron to 0.5-s pulses of individual components of skin odor in A. aegypti and A. gambiae, where n 4-7 (right).
  • FIG. Id is a graph illustrating the temporal response of the A. aegypti cpA mean firing frequency to a 1-s stimulus counted in 100-ms bins, where average
  • FIG. le is a graph illustrating A. aegypti cpA responses to representative
  • activating odorants are dose dependent, in which all odorants except C0 2 is dissolved in paraffin oil (PO) at 10 ⁇ 2 except where indicated, and error bars are s.e.m.
  • FIG. 2a is a comparison of chemical structures of butyraldehyde, butyric
  • FIG. 2b depicts representative cp responses to 0.5-s pulses of indicated
  • FIG. 2c is a bar graph illustrating the mean odorant-evoked responses of
  • FIG. 2d is a bar graph
  • n 6 individuals, 1-4 sensilla surveyed per individual; analysed by nested ANOVA, and baseline refers to cpA activity in the
  • FIG. 2e is a graph illustrating averaged traces and FIG. 2f is a graph
  • EAG mean electroantennograph
  • FIG. 2g depicts sample traces and mean cpA responses to 0.5-s pulses of
  • n 4 individuals, 2-3 sensilla surveyed per individual, and
  • FIG. 2h is a schematic of wind tunnel assay, where human odor was
  • FIGS. 2i-k are bar graphs illustrating the proportion of butyryl chloride
  • FIG. 3a is a schematic providing an overview of the cheminformatics
  • FIG. 3b depicts representative traces and mean responses of the A. aegypti cpA neuron to 0.5-s pulses of 138 predicted compounds screened using single- sensillum recordings, in which odorants were diluted to 10 ⁇ 2 in paraffin oil or water,
  • n 2-6, and error bars are s.d.
  • FIG. 3c depicts representative traces and mean percent inhibition of the A.
  • FIG. 3d depicts representative traces from the A. aegypti cp sensillum to 1- s pulses of 0.15% C0 2 prior to and following a 3-s exposure to either solvent (paraffin oil) or (E)-2-methylbut-2-enal (10 1 ).
  • FIG. 3e is a graph illustrating the cpA baseline activity in the 1 s prior to
  • each stimulus is elevated following exposure to odorant, where error bars are s.e.m.
  • FIG. 3f is a bar graph illustrating the mean responses of the cpA neuron to
  • FIG. 4a is a graph illustrating the dose response of inhibition of A. aegypti cpA neuron when a 1-s stimulus of ethyl pyruvate is overlaid on a 3-s stimulus of
  • FIG. 4b depicts representative trace and mean response when a 1-s
  • FIG. 4c depicts representative images (left) of hand-in-cage assay mesh
  • FIG. 4d is a graph illustrating the dose responses of the cpA neuron to
  • FIG. 4f depicts representative traces of repeated 1-s stimuli of
  • FIG. 4g is a schematic of two-choice greenhouse experiments with two
  • FIG. 4h is a graph illustrating the mean number of mosquitoes/trial
  • FIG. 4i is a graph illustrating the preference index for C0 2 and
  • FIG. 5a is a graph illustrating the principle component analysis (PCA) of
  • olfactory receptors (AgOrs).
  • FIG. 5b illustrates the PCA analysis of FIG. 5a relabelled by chemical
  • FIG. 5c is a hierarchical clustering of odorants that interact with cpA with inter-chemical distances generated from activity-optimized descriptors, and sample
  • FIG. 5d provides an overview of the support vector machine (SVM)
  • FIG. 5e is a graph illustrating the receiver-operating-characteristic curve
  • FIG. 5f is a bar graph illustrating the mean responses of the A. aegypti cpA neuron to 0.5-s pulses of 22 newly predicted compounds screened as in FIG. 3b,
  • n 2-5.
  • FIG. 6 is an exemplary model for cpA-mediated host-seeking and odorants that disrupt it, in which inhibitors may be used to block attraction to both C0 2 and
  • skin odor (MASK) and activators may be used as lures for traps (PULL).
  • FIG. 7a is a schematic of a human odor delivery system.
  • FIG. 7b is a schematic of an activation screen.
  • the activation screen For the activation screen,
  • Black arrows indicate switch in airflow during stimulus delivery.
  • FIGS. 8a-8f illustrate an electrophysiological analysis of cpA action
  • FIG. 9a illustrates sample traces from repeated stimulus experiments: 1-s
  • FIG. 9b illustrates sample traces and mean cpA responses to 0.5-s pulses
  • FIG. 9c illustrates averaged traces of EAG responses to 0.5-s stimuli of
  • FIG. 9e is a schematic of the apparatus used to assay short-range attraction to heat and humidity.
  • FIG. 9f illustrates mosquitoes' tendency to rest at the top surface of the
  • FIG. 10a is a schematic of the wind tunnel used in the wind tunnel assays showing the mosquito release chamber, human foot odor bead stage, and retracted
  • FIG. 10b shows histograms quantifying the number of mosquitoes that
  • FIG. 10c shows plots where each row indicates flight behavior of each
  • FIG. l ib illustrates the mean responses of the cpA neuron to different
  • FIG. 11c illustrates that the temporal response profiles elicited by repeated exposures to cyclopentanone are similar to those elicited by C0 2 . Individuals were
  • the repellants may be any organic compound that are repellents for at least one arthropod species.
  • the repellants may be any organic compound that are repellents for at least one arthropod species.
  • the repellants may be any organic compound that are repellents for at least one arthropod species.
  • the repellants may be any organic compound that are repellents for at least one arthropod species.
  • the repellants may be any organic compound that are repellents for at least one arthropod species.
  • Arthropods are invertebrate animals characterized as having an
  • arthropod includes any invertebrate animal from the Classes of Insecta, Arachnida,
  • arthropoda Diplopoda, Chilopoda, Crustacea, and Xiphosura.
  • arthropoda Diplopoda, Chilopoda, Crustacea, and Xiphosura.
  • arthropoda Diplopoda, Chilopoda, Crustacea, and Xiphosura.
  • arthropoda Diplopoda, Chilopoda, Crustacea, and Xiphosura.
  • insects and arachnids that are exoparasitic sanguinivorous feeding pests, including any insect from the Order Diptera, such as mosquitoes, and any arachnid
  • mosquitoes include Anopheles,
  • an example of the Anopheles includes anopheles
  • Culex examples include Culex quinquefasciatus, Culex
  • the Aedes include Aedes albopictus and Aedes aegypti.
  • An example of the Armigeres includes Armigeres subalbatus.
  • the screening methods can be used to identify one or more arthropods
  • Gr2- and/or Gr3-expressing_neuron e.g. , that may be a cpA neuron.
  • the method includes: a) providing a candidate compound and a skin
  • the screening methods can also be used to identify one or more arthropod attractants based on activating a Grl-, Gr2- and/or Gr 3-expressing_neuron.
  • the screening methods provided herein may be used to screen one
  • candidate compounds may be natural or synthetic compounds.
  • the one or more candidate compounds may be from bacterial, fungal, plant and animal
  • candidate compounds can also be chemically-modified compounds, such as by
  • the one or more candidates compounds screened in the methods described herein may be preselected based on one or more criteria. For example, a set of compounds with
  • a computation method may be used to select such candidate compounds.
  • Other criteria used for selecting the one or more candidate compounds include the environmental impact of the compounds, regulatory approval of the compounds for human consumption (e.g. , FDA- approval), and the
  • smell of the compounds e.g. , natural fragrances, aromas, or odors.
  • candidate compounds may be an individual odor or a blend of odors.
  • vertebrate odor e.g. , human odor
  • odor is a blend of hundreds
  • FIG. 1A may include, for example, the compounds in FIG. 1A or any combinations thereof.
  • Vertebrate odor may also include skin odor blend collected from placing an adsorbent or absorbent material in contact with skin, or placed in the headspace above the skin, or a gas passed over the skin, Or skin brought into close vicinity of the cpA.
  • the sample provided in the methods described herein may include a Grl-,
  • the neuron may include three conserved seven- transmembrane domain proteins encoded by members of the gustatory receptor (Gr)
  • Such neuron may be a cpA neuron, which is an
  • olfactory receptor neuron housed in specialized capitate peg (cp) sensilla and express the C0 2 receptor.
  • cp capitate peg
  • mosquitos Aedes aegypti
  • cpA neurons are located in
  • the neuron may be activated in response to a vertebrate skin odor.
  • the sample includes a cell expressing Grl, Gr2, Gr3, or a
  • the neurons of the present disclosure may include a
  • Grl receptors are known in the art. The Grl receptors of the present invention
  • Grl receptor selected from, for example, Aedes aegypti
  • a homolog or an ortholog or any known or putative Grl receptor may also be used in the methods and systems described herein.
  • a homolog may be a protein
  • nucleic acid sequence that encodes that protein has a similar sequence to the
  • nucleic acid sequence that encodes a known or putative Grl receptor, or a protein
  • Grl homologs may have functional, structural or genomic
  • an ortholog is an evolutionarily-related polypeptide or polynucleotide sequence in different species that have similar sequences and
  • a homolog and/or ortholog of a Grl receptor is a
  • a homolog of a Grl receptor is a protein whose amino acid sequence has at least 30%, 40%, 50% 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%,
  • the Grl receptor may be from one or more arthropod species.
  • the Grl receptor is a homolog or ortholog of the
  • the Grl receptor from Aedes aegypti. In some embodiments, the Grl receptor has at least
  • sequences or between two nucleic acid sequences.
  • sequences can be aligned for optimal comparison purposes.
  • gaps can be introduced in one or both of a first and a second amino acid or
  • nucleic acid sequence for optimal alignment and non-homologous sequences can be any nucleic acid sequence for optimal alignment and non-homologous sequences.
  • corresponding amino acid positions or nucleotide positions can then be compared.
  • the neurons of the present disclosure may include a
  • Gr2 receptors are known in the art. The Gr2 receptors of the present invention
  • Gr2 receptor selected from, for example, Aedes aegypti
  • a homolog or an ortholog or any known or putative Gr2 receptor may also be used in the methods and systems described herein.
  • a homolog may be a protein
  • nucleic acid sequence that encodes that protein has a similar sequence to the
  • nucleic acid sequence that encodes a known or putative Gr2 receptor, or a protein
  • amino acid sequence is similar to the amino acid sequence of a known or
  • Gr2 homologs may have functional, structural or genomic
  • a homolog and/or ortholog of a Gr2 receptor is a
  • a homolog of a Gr2 receptor is a protein whose amino acid sequence has at least 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%,
  • the Gr2 receptor may be from one or more arthropod species.
  • the Gr2 receptor is a homolog or ortholog of the
  • the Gr2 receptor from Aedes aegypti.
  • the Gr2 receptor has at least
  • the neurons of the present disclosure may include a
  • Gr3 receptor is known in the art.
  • the Gr3 receptors of the present invention are known in the art.
  • the Gr3 receptors of the present invention are known in the art.
  • a Gr3 receptor selected from, for example, Aedes aegypti,
  • a homolog or an ortholog or any known or putative Gr3 receptor may also be used in the methods and systems described herein.
  • a homolog may be a protein
  • nucleic acid sequence that encodes that protein has a similar sequence to the
  • nucleic acid sequence that encodes a known or putative Gr3 receptor, or a protein
  • amino acid sequence is similar to the amino acid sequence of a known or
  • Gr3 homologs may have functional, structural or genomic
  • a homolog and/or ortholog of a Gr3 receptor is a
  • a homolog of a Gr3 receptor is a protein whose amino acid sequence has at least 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%,
  • the Gr3 receptor may be from one or more arthropod species.
  • the Gr3 receptor is a homolog or ortholog of the
  • the Gr3 receptor from Aedes aegypti.
  • the Gr3 receptor has at least
  • neuron may be measured by any suitable methods and techniques known in the art.
  • Suitable methods and techniques include, for example, measuring
  • EAGs electroantennograms
  • EPGs can be used to detect the aggregate electrical activities from a large number of neurons in response to odors. Another method of detecting skin odor activation is
  • candidate compounds to determine whether a candidate compound is an arthropod
  • a candidate compound is selected as an arthropod
  • a Grl-, Gr2- and/or GrJ-expressing neuron a Grl-, Gr2- and/or GrJ-expressing neuron.
  • a Grl-, Gr2- and/or GrJ-expressing neuron a Grl-, Gr2- and/or GrJ-expressing neuron.
  • candidate compound is selected as an arthropod repellent based on at least 75%, 80%,
  • a candidate compound is selected as an arthropod
  • a candidate compound repellent based on the ability of the candidate compound to inhibit the detection of the skin odor by the Grl-, Gr2- and/or Gr3-expressing_neuron.
  • a candidate compound repellent based on the ability of the candidate compound to inhibit the detection of the skin odor by the Grl-, Gr2- and/or Gr3-expressing_neuron.
  • One or more candidate compounds may be identified as an arthropod
  • a candidate compound is selected as an arthropod attractant
  • the system includes: a) a sample that includes a
  • Grl-, Gr2- and/or Gr J-expressing_neuron b) a skin odor; and c) one or more
  • the skin odor may be an individual odor or the skin
  • odor may be made up of a plurality of odors.
  • the Grl-, Gr2- and/or Gr3-expressing_neuron may be from an arthropod or, in certain embodiments, an insect.
  • sf-3391325 Attorney Docket No. 677032000740 the Grl-, Grl- and/or Gr3-expressing_neuron.
  • compound is selected as an arthropod attractant based on at least 75%, 80%, 85%,
  • Gr2- and/or Gr3-expressing neuron One or more of such compounds may be used in a composition that is an arthropod repellent.
  • the compound has a structure of formula (I):
  • X 1 and X 2 are each independently selected from the group consisting of O, S
  • R 1 and R 2 are each independently selected from the group consisting of H, D, halide, optionally substituted aliphatic group, and optionally substituted hetero- aliphatic group; or R 1 and R 2 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • the compound of formula (I) is other than methyl acetate.
  • aliphatic compounds include any non-aromatic compound selected from any non-aromatic group consisting of:
  • aliphatic compounds include (Ci to Cis)alkyls, (Ci to C15)
  • alkenyls (Ci to Cis)alkynyls, cycloalkyls, cycloalkenyls, and cycloalkynyls.
  • hetero-aliphatic groups include any aliphatic compounds in
  • hetero-aliphatic groups may include (Ci to Ci 4 )hetero-alkyls,
  • Optionally substituted groups which contain halogens may include, for example,
  • Optionally substituted groups which contain oxygen may include, for example, hydroxyls, carbonyls, aldehydes, haloformyls,
  • Optionally substituted groups which contain nitrogen may include, for example,
  • sulfur may include, for example, thiols, sulfides, disulfides, sulfoxides, sulfones,
  • Optionally substituted groups which contain phosphorus may include, for example, phosphinos, phosphonos, and
  • phosphates optionally substituted groups which contain boron, such as boronos,
  • silicon may include, for example, silyl ethers, silicates, siloxanes, and silanes.
  • the compound has a structure of formula (la):
  • R 1 and R 2 are each independently selected from the group consisting H, OH,
  • heteroaromatic ring system having 3 to 6 ring carbon atoms.
  • the aliphatic or hetero-aliphatic groups may be straight or branched, and
  • R 2 or R 1 is H, D, halide, optionally substituted C 2+ aliphatic group, and
  • R 1 and R 2 are each independently
  • R 1 and R 2 can be linked
  • heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • R 1 is a cyclic group having 4 to 8 ring carbon atoms, then the cyclic group is other than optionally substituted aryl.
  • R 2 is an optionally substituted aliphatic
  • R 2 is a cyclic group having 4 to 8 ring carbon atoms, then the cyclic group is other than aryl substituted with an optionally substituted amino group.
  • the compound has a structure of formula (lb):
  • R 1 and R 2 are each independently selected from the group comprising H, OH,
  • R 1 and R 2 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or
  • heteroaromatic ring system having 3 to 6 ring carbon atoms.
  • R 1 and R 2 are each independently
  • R 1 and R 2 can be
  • the compound of formula (I) is selected from methyl propanoate, methyl 2-methylpropanoate, propyl acetate, ethyl acetate, propyl formate, prop-2-enyl-propanoate, 2-methylpropyl formate, methyl butanoate, methyl acetate,
  • the compound of formula (I) is selected from 2,2- dimethyl-3-(2-methyl-propenyl)-cyclopropanecarboxylic acid ethyl ester, acetic acid
  • the compound has a structure of formula (II):
  • X 3 and X 4 are each independently selected from the group consisting O, S and
  • R 3 and R 4 are each independently selected from the group consisting of H, D, a halide, and optionally substituted aliphatic groups, or R 3 and R 4 can be linked
  • the compound has a structure of formula (Ila):
  • R 3 and R 4 are each independently selected from the group consisting of H,
  • R 3 and R 4 carbon atoms; or R 3 and R 4 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • the compound of formula (II) is selected from 3- methylcyclopentane- 1 ,2-dione, 3 ,4-dimethylcyclopentane- 1 ,2-dione, 2-oxopentanoic acid, and 2-oxopropanal.
  • the compound has a structure of formula (III):
  • R 5 and R 6 are each independently selected from the group consisting of H, D, a halide, and optionally substituted aliphatic group;
  • R 7 is selected from the group consisting of an optionally substituted aliphatic
  • R 5 and R 6 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; or
  • R 6 and R 7 can be linked together to form an optionally substituted ring
  • cycloalkenyl selected from the group consisting of cycloalkenyl, aryl, and heterocycle.
  • R -R are each independently
  • R 5 and R 6 can be linked together to form an optionally substituted
  • aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring
  • R 6 and R 7 can be linked
  • heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound of formula (III) is selected from
  • the compound of formula (III) is selected from
  • the compound has a structure of formula (IV):
  • R 8 , R 9 and R 10 are each independently selected from the group consisting of H,
  • the compound has a structure of formula (IVa):
  • R 8 and R 9 are each independently selected from the group consisting of H,
  • R 8 and R 9 can be linked together to form an optionally substituted
  • aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring
  • the compound of formula (IV) is selected from 4- hydroxy-2,3-dimethyl-2H-furan-5-one, 2-hydroxypropanoic acid, and 3- hydroxybutan-2-one.
  • the compound of formula (IV) is selected from 4- ethylidene-7-hydroxy-6,7,14-trimethyl-2,9-dioxa-14-aza-bicyclo[9.5.1]heptadec-ll- ene-3,8,17-trione, 2-hydroxy-2-(l-hydroxy-ethyl)-3-methyl -butyric acid 7-hydroxy- 5,6,7,7a-tetrahydro-3H-pyrrolizin-l-ylmethyl ester, and 2-hydroxy-2-(l-methoxy- ethyl)-3-methyl-butyric acid 7-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-l-ylmethyl ester.
  • the compound has a structure of formula (V):
  • X 6 is selected from the group consisting of O, S, and NH;
  • R 11 and R 12 are each independently selected from the group consisting of H,
  • R 11 and R 12 can be
  • the compound has a structure of formula (Va):
  • R 11 and R 12 are each independently selected from the group consisting of H,
  • R 11 and R 12 can be linked together to form an optionally
  • the compound of formula (V) is selected from ethyl 2- oxopropanoate, methyl 2-oxopropanoate, 4-hydroxy-2,3-dimethyl-2H-furan-5-one,
  • the compound has a structure of formula (VI):
  • X 7 , X 8 , and X 9 are each independently selected from the group consisting of
  • R 13 and R 14 are each independently selected from the group consisting of H,
  • R 13 and R 14 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • the compound has a structure of formula (Via):
  • R and R are each independently selected from the group consisting of H,
  • R 13 and R 14 can be linked together to form an optionally
  • the compound of formula (VI) is selected from
  • the compound has a structure of formula (VII):
  • X is selected from the group consisting of O, S, and NH;
  • R 15 and R 16 are each independently selected from the group consisting of H,
  • R 15 and R 16 can be
  • the compound has a structure of formula (Vila):
  • R 15 and R 16 are each independently selected from the group consisting of H,
  • R 15 and R 16 can be linked together form an optionally substituted
  • aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring
  • the compound has a structure of formula (VIII):
  • X 11 is selected from the group consisting of OH, SH, and N3 ⁇ 4;
  • R 17 , R 18 , and R 19 are each independently selected from the group consisting of
  • R 20 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • the compound has a structure of formula (Villa):
  • R , R , and R are each independently selected from the group consisting of
  • R 19 can be linked together to form an optionally substituted aliphatic
  • heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon
  • the compound has a structure of formula (IX):
  • X -X are each independently selected from the group consisting of C, N, O, and S;
  • R 20 -R 25 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl,
  • R 20 -R 25 are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or two or more of R 20 -R 25 can
  • the compound has a structure of formula (IXa):
  • R , R , R , and R" J are each independently selected from the group
  • W" and R" J can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; and/or
  • R 22 and R 23 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • R , R , R , and R are each
  • R 22 and R 23 can be substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • R 22 and R 23 can be
  • the compound has a structure of formula (IXb):
  • R and R -R are each independently selected from the group consisting of
  • R 22 -R 25 can be linked together to form one or more optionally substituted
  • cycloalkyl cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • R and R -R are each
  • two or more of R"" and R -R can be linked together to form an optionally substituted aliphatic or heteroaliphatic, aromatic or
  • heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound has a structure of formula (IXc):
  • R and R -R are each independently selected from the group consisting of
  • R 22 -R 25 can be linked together to form one or more optionally substituted
  • cycloalkyl cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • R 20 and R 22 -R 25 are each
  • two or more of R 2 ⁇ 0 and R 22 -R 2"5 J can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound has a structure of formula (IXd):
  • R 21 is selected from the group consisting of H, D, a halides, an optionally
  • the compound has a structure of formula (X):
  • X -X are each independently selected from the group consisting of C, O, N, and S;
  • R groups are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or two or more R groups from
  • cycloalkyl can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle;
  • the compound has a structure of formula (Xa):
  • R and R " R are each independently selected from the group consisting of
  • R H, D, a halides, or an optionally substituted aliphatic group; or R " R can be linked
  • R and R " R are each
  • the compound has a structure of formula (Xb):
  • R , and R -R are each independently selected from the group consisting of
  • R -R JU can be linked together to form one or more optionally substituted
  • cycloalkyl cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • R and R -R are each
  • the compound has a structure of formula (Xc):
  • R , and R -R are each independently selected from the group consisting of
  • R -R JU can be linked together to form one or more optionally substituted
  • cycloalkyl cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • R , and R -R are each
  • R and R -R are each
  • the compound has a structure of formula (XI):
  • R -R are each independently selected from the group consisting of H, D, a
  • R 31' -R 34' are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or two or more of R 31 -R 34 can
  • the compound has a structure of formula (XIa):
  • R 31 -R 34 are each independently selected the group consisting of H, D, a
  • cycloalkenyl cycloalkynyl, aryl, or heterocycle.
  • R 31" R 34 are each independently
  • R 33" R 36 can be linked together to form an optionally substituted aliphatic or heteroaliphatic, aromatic, heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound has a structure of formula (XII):
  • W is -NR c R d or -CR c R d R e ;
  • a m is an aliphatic group
  • each A" is independently an aliphatic group
  • each R a , R b , R c , R d and R e is independently H or an aliphatic group
  • each R n is independently H or an aliphatic group
  • x is an integer greater than or equal to 1 ;
  • W is -NR c R d .
  • x is 0 to 8.
  • the compound of formula (XII) is other than
  • a m is an alkyl. In some embodiments, each A" is
  • a m is a (C1-C5) alkyl. In certain embodiments,
  • each A n is a (CI -C5) alkyl.
  • x is 1 or 2;
  • W is -NR c R d ;
  • each R a , R b , R c , R d , and R n is H;
  • each A" and A m is independently alkyl.
  • the compound has a structure of formula (XIIA)
  • n is 1 to 10, or 1 to 8, or 1 to 5. In one embodiment, n is 1, 2, 3, or 4.
  • m is 1 to 10, or 1 to
  • m 1, 2, 3, or 4.
  • p is 1 to 10, or 1 to 8, or 1 to 5.
  • p is 1, 2, 3, or 4.
  • the compound is:
  • the compound is:
  • compositions comprising one or more compounds of formula (I)-(XII).
  • the composition includes two or more
  • the composition includes two or more compounds of formula (Xb) and
  • compositions including one or more, two or more, or three or more compounds
  • compositions may further include thickeners, buffering agents,
  • chelating agents preservatives, fragrances, moisturizers, antioxidants, gelling agents, stabilizers, surfactants, emollients, carriers, coloring agents, aloe vera, waxes,
  • lanolins other penetration enhancers and mixtures thereof, therapeutically or
  • the composition may be formulated for the topical administration of the composition to the skin of a subject (e.g. , a human).
  • a subject e.g. , a human
  • compositions described herein may be solid-based, liquid-based, gas- based, or a mixture thereof.
  • Liquid-based formulations may be aqueous-based or non- aqueous-based (e.g. , organic solvents), or combinations thereof, and may be
  • compositions may also be formulated to
  • compositions described herein may further include one or more carrier formulation agents, including commercially-available organic and inorganic liquids
  • organic liquid carriers include liquid aliphatic hydrocarbons (e.g. , pentane, hexane,
  • liquid hydrocarbons examples include oils produced by the distillation of
  • kerosene oils that are obtained by fractional distillation of petroleum.
  • petroleum oils include those generally referred to as agricultural spray oils (e.g. , light and medium spray oils that include middle fractions in the distillation of petroleum
  • oils which are only slightly volatile.
  • oils are usually highly refined and may be selected from
  • organic liquid carriers may include, for example, liquid terpene hydrocarbons
  • terpene alcohols such as alpha-pinene, dipentene, and terpineol.
  • Suitable carriers may include, for example, aliphatic and aromatic
  • the carrier may include, for example, conventional emulsifying agents, which can be used for facilitating the dispersal of the formulation or composition to
  • Aliphatic monohydric alcohols may include, for example, methyl, ethyl, normal-propyl, isopropyl, normal- butyl, sec-butyl, and ieri-butyl alcohols.
  • Suitable alcohols may include, for example, glycols (e.g. , ethylene and propylene glycol) and pinacols.
  • alcohols may include, for example, glycerol, arabitol, erythritol, and sorbitol.
  • Suitable cyclic alcohols may include, for example, cyclopentyl and cyclohexyl alcohols.
  • Solid carriers that can be used in the compositions described herein may be any suitable solid carriers.
  • finely divided solid inorganic carriers may include, for example, siliceous minerals
  • siliceous materials such as silica aerogels and precipitated and fume silicas.
  • finely divided solid organic materials may include cellulose, sawdust,
  • waxy solids include waxy solids, gels (e.g. , petroleum jelly), and lanolin, and mixtures of liquid
  • compositions or formulations described herein may
  • stabilizer formulation agents known in the art, including, for example, ieri-butyl sulfinyl dimethyl dithiocarbonate.
  • compositions described herein may include adjuvant formulation
  • agents used in personal care product formulations such as thickeners, buffering
  • compositions or formulations disclosed herein may include, for example,, fungicides, sunscreening agents, sunblocking agents, vitamins, tanning agents, plant extracts,
  • anti-inflammatory agents include anti-oxidants, radical scavenging agents, retinoids, alpha- hydroxy acids, emollients, antiseptics, antibiotics, antibacterial agents, and
  • compositions described herein may further comprise
  • insect repellent formulation agents known in the art including, for example benzil, benzyl benzoate, 2,3,4,5-bis(butyl-2-ene) tetrahydrofurfural,
  • butoxypolypropylene glycol N-butylacetanilide, normal-butyl-6,6-dimethyl-5,6- dihydro- l,4-pyrone-2-carboxylate, dibutyl adipate, dibutyl phthalate, di-normal-butyl succinate, ⁇ , ⁇ -diethyl-meta-toluamide, dimethyl carbate, dimethyl phthalate, 2-ethyl- 2-butyl- 1 ,3-propanediol, 2-ethyl- 1 ,3-hexanediol, di-normal-propyl
  • compositions described herein may include other known compatible materials
  • active formulation agents including, for example, insecticides, acaricides,
  • rodenticides rodenticides, fungicides, bactericides, nematocides, herbicides, fertilizers, and
  • the agents may be in the form of
  • compositions described herein may be administered in combination with other insect control agents.
  • the compositions may be administered in combination with other insect control agents.
  • the compositions may be administered in combination with other insect control agents.
  • the compositions may be administered in combination with other insect control agents.
  • the compositions may be administered in combination with other insect control agents.
  • the compositions may be administered in combination with other insect control agents.
  • the compositions may be administered in combination with other insect control agents.
  • the compositions may be administered in combination with other insect control agents.
  • the compositions may be administered in combination with other insect control agents.
  • the compositions may be administered in combination with other insect control agents.
  • the compositions may be administered in combination with other insect control agents.
  • the compounds identified by the methods and systems herein may also be administered with chemosterilants.
  • the ⁇ vary depending on the application. For example, in some embodiments, the ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • compositions described herein has at least about 0.0001 % by weight of one or more of the compounds identified by the methods or systems described herein, or about
  • compositions described herein contain
  • arthropod' s e.g. , insect's
  • composition suitable for applying to the surface of an object or subject, such as to a
  • compositions for topical applications e.g., topical applications
  • sf-3391325 Attorney Docket No. 677032000740 include a vehicle, such as an alcohol based solvent, a lotion such as numerous skin
  • the composition has a surface evaporation rate of at least a minimum effective evaporation rate for at least 1, 2, 3, 4, 5, 6, 7, 8,
  • the compounds described herein are generally mixed in a dermatologically acceptable carrier, such pharmaceutically acceptable creams, polymers, lotions, gels, and/or
  • the pharmaceutically acceptable carriers may further provide water
  • a carrier(s) for any formulation with one or more compounds of the disclosure include solubility, commercial availability, cost, evaporation rate,
  • compositions and compounds of the disclosure do not only include human
  • subjects but include canines, equines, bovines and other animals subject to
  • micro-encapsulated may be micro-encapsulated to control rates of evaporation from the surface of a
  • a precursor molecule may be prepared,
  • olfactory receptor modulating compounds of the disclosure may be, for example, by

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Abstract

Provided herein are screening methods for identifying compounds for use as an arthropod repellent based on the masking or inhibition of the detection of the skin odor by a cpA neuron. Provided herein are also screening methods for identifying compounds for use as an arthropod attractant based on activation of the cpA neuron. Further provided are one or more compounds identified using the screening methods described herein, and compositions containing such compounds.

Description

Attorney Docket No. 677032000740
METHODS FOR IDENTIFYING ARTHROPOD REPELLENTS, AND
COMPOUNDS AND COMPOSITIONS IDENTIFIED BY SUCH METHODS
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional Patent Application No.
61/799,734, filed March 15, 2013, which is incorporated herein by reference in its
entirety.
FIELD
[0002] The present disclosure relates generally to the field of arthropod repellents and attractants, and more specifically to methods of identifying such repellents based on affecting the detection of human skin odors in arthropods.
BACKGROUND
[0003] Blood-feeding insects, such as mosquitoes, transmit deadly pathogens like malaria parasites, dengue viruses, and filarial worms to hundreds of millions of people every year. Insect repellents can be very effective in reducing vectorial capacity by
blocking the contact between blood- seeking insects and humans; however, they are
seldom used in disease-prone areas of Africa and Asia due to high costs and need for continuous application on skin.
[0004] N,N-Diethyl-m-toluamide (DEET) is an example of an insect repellent
used in the developed world for more than sixty years. The use of DEET as an insect repellent, however, has several drawbacks. For example, DEET is a solvent capable
of melting several forms of plastics, synthetic fabrics, painted and varnished surfaces
(Krajick et al., Science, 313: 36, 2006). Additionally, DEET has been shown to
inhibit mammalian cation channels and human acetylcholinesterase, which is also
inhibited by carbamate insecticides commonly used in disease endemic areas (Corbel et al., BMC Biol, 7, 2009). These concerns are enhanced by the requirement of direct and continuous application of DEET to every part of exposed skin in concentrations
that can be as high as 30-100%. Several instances of increased resistance to DEET
have also been reported in flies, Anopheles albimanus, and Aedes aegypti (Reeder et
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sf-3391325 Attorney Docket No. 677032000740 al, JEcon Entomol, 94: 1584, 2001; Klun et al, J Med Entomol, 41: 418, 2004;
Stanczyk et al, Proc Natl Acad Sci USA, 107: 8575, 2010). Moreover, mosquito
strains with resistance to pyrethroid insecticides, the main line of defense against
mosquitoes in developing countries, are spreading (Butler et al, Nature, 475: 19,
2011). The other major barrier in developing new repellents is the time and cost of
development, which can take more than $30 million and several years to identify new compounds that not only repellent to insects, but are also safe for human use.
[0005] Thus, what is needed in the art are alternative compounds to DEET that
can be used as insect repellents but are safe for human use, and methods of identifying such alternatives.
BRIEF SUMMARY
[0006] In one aspect, provided is a method for identifying a compound that is a
repellent for at least one arthropod species, by a) providing a candidate compound and a skin odor; b) providing a sample that includes a neuron, wherein the neuron
expresses at least one of Grl, Gr2, and Gr3 or any orthologs thereof; c) contacting the candidate compound with the sample; d) measuring the detection of the skin odor by the neuron; e) comparing the detection of the skin odor by the neuron after contact
with the candidate compound to the detection of the skin odor by the neuron in the
absence of the candidate compound; and f) identifying a compound that is a repellent for at least one arthropod
species by determining whether or not the candidate compound masks or inhibits the detection of the skin odor by the neuron.
[0007] In some embodiments, the neuron expresses at least one of AgGr22,
AgGr23, and AgGr24 in Anopheles gambiae (also called Grl, Gr2 and Gr3), or any
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sf-3391325 Attorney Docket No. 677032000740 insect orthologs thereof. In some embodiments, the skin odor is an individual odorant or the skin odor comprises a plurality of odorants. In one embodiment, the neuron is a cpA neuron in maxillary palps of mosquitoes. In certain embodiments, the neuron is from an arthropod. In certain embodiments, the neuron is from an insect.
[0008] In some embodiments, the compound that is a repellent for at least one
arthropod species is identified by determining whether or not the candidate compound masks or inhibits at least 75% of the detection of the skin odor by the neuron. In
certain embodiments, the compound is identified in an in vitro assay or in vivo assay.
In some embodiments, the activity of the neuron is measured by one or more
electrophysiological parameters, one or more activity imaging parameters, or any
combinations thereof.
[0009] Provided herein is also a composition that includes one or more compound identified according to any of the methods described above.
[0010] Provided is also a system that includes: a) a sample comprising a neuron, wherein the neuron expresses at least
one of Grl, Gr2, and Gr3, or any orthologs thereof; b) a skin odor; and c) one or more compounds that each is a repellent for at least one
arthropod species, wherein the one or more compounds each masks or inhibits the
detection of the skin odor by the neuron during or after exposure to the one or more
compounds.
[0011] In some embodiments, the skin odor is an individual odorant or the skin
odor comprises a plurality of odors. In some embodiments, the neuron is a cpA
neuron. In certain embodiments, the neuron is from an arthropod. In certain
embodiments, the neuron is from an insect. In some embodiments, the one or more
compounds each masks or inhibits at least 75% of the detection of the skin odor by
the neuron.
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sf-3391325 Attorney Docket No. 677032000740
[0012] Provided is also a composition for use as an arthropod repellent, that
includes two or more compounds selected from the compounds of formulae (la), (Va) and (III):
Figure imgf000006_0001
wherein:
R1 and R2 are each independently selected from the group consisting H, OH,
SH, an optionally substituted aliphatic or hetero- aliphatic group having 1 to 6 carbon atoms, and a cyclic group having 4 to 8 ring carbon atoms; or R1 and R2 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or
heteroaromatic ring system having 3 to 6 ring carbon atoms,
Figure imgf000006_0002
wherein:
R11 and R12 are each independently selected from the group consisting of H,
OH, SH, and an optionally substituted aliphatic or hetero- aliphatic group having 1 to
4 carbon atoms; or R11 and R12 can be linked together to form an optionally
substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms,
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sf-3391325 Attorney Docket No. 677032000740
Figure imgf000007_0001
wherein:
R5 and R6 are each independently selected from the group consisting of H, D, a halide, and optionally substituted aliphatic group; and
R7 is selected from the group consisting of an optionally substituted aliphatic
group; or
R5 and R6 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; or
R6 and R7 can be linked together to form an optionally substituted ring
selected from the group consisting of cycloalkenyl, aryl, and heterocycle, or any combinations thereof.
[0013] In some embodiments, the composition includes: i) one or more
compounds of formula (la); and ii) one or more compounds selected from compounds of formulae (Va) and (III), or any combination thereof.
[0014] In certain embodiments, the one or more compounds of formula (la) are
one or more alkyl 2-oxopropanoates. In one embodiment, the one or more alkyl 2- oxopropanoates are selected from the group consisting of ethyl 2-oxopropanoate and
methyl 2-oxopropanoate.
[0015] Provided is also a composition for use an arthropod repellent, that includes one or more compounds of formula (XII):
Figure imgf000007_0002
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sf-3391325 Attorney Docket No. 677032000740 wherein:
W is -NRcRd;
Am is an aliphatic group;
each A" is independently an aliphatic group;
each Ra, Rb, Rc and Rd is independently H or an aliphatic group;
each Rn is independently H or an aliphatic group; and
x is an integer greater than or equal to 1 ;
[0016] In some embodiments, x is 0 to 8. In certain embodiments, x is 1 or 2; W
is -NRcRd; each Ra, Rb, Rc, Rd, and Rn is H; and each A" and Am is independently
alkyl.
[0017] In one embodiment, the compound is:
Figure imgf000008_0001
, or a combination thereof.
[0018] Provided herein is also a composition for use as an arthropod repellent that includes: i) one or more pyruvate inhibitors selected from the compounds of Table A,
Group II; and ii) one or more super activators selected from the compound of Table
A, Group III.
[0019] In some embodiments, the composition is formulated into a lotion, a
cream, a spray, a dust, a vaporizer, a treated mat, a treated outerwear, an oil, a candle, or a wicked apparatus.
[0020] Provided is also a composition for use as an arthropod attractant, that
includes two or more of the compounds of formulae (la), (Xb), (Xc), and (XIa):
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sf-3391325 Attorney Docket No. 677032000740
Figure imgf000009_0001
wherein:
R1 and R2 are each independently selected from the group consisting H, OH,
SH, an optionally substituted aliphatic or hetero- aliphatic group having 1 to 6 carbon atoms, and a cyclic group having 4 to 8 ring carbon atoms; or R1 and R2 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or
heteroaromatic ring system having 3 to 6 ring carbon atoms,
Figure imgf000009_0002
wherein:
R26, and R28-R30 are each independently selected from the group consisting of
H, D, a halides, and an optionally substituted aliphatic group; or two or more of R26, and R 28 -R 3J0U can be linked together to form one or more optionally substituted
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle,
Figure imgf000009_0003
wherein:
R 26 , and R 28 -R 3J0U are each independently selected from the group consisting of
H, D, a halides, and an optionally substituted aliphatic group; or two or more of R26
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sf-3391325 Attorney Docket No. 677032000740 and R -R can be linked together to form one or more optionally substituted
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle,
Figure imgf000010_0001
wherein:
R31-R34 are each independently selected the group consisting of H, D, a
halides, and an optionally substituted aliphatic group; and/or two or more of R31-R34
can be linked together to form one or more optionally substituted cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, or heterocycle, or any combination thereof.
[0021] Provided is also a composition for use as an arthropod attractant that
includes: i) one or more compounds selected from thiophene, cyclopentanone, 1H- pyrrole, hex-5-en-2-one, and methyl 2-methylpropanoate; and ii) one or more compounds selected from compounds of formulae (la),
(Xb), (Xc), and (XIa), or any combination thereof.
[0022] In some embodiments, one or more compounds selected from thiophene, lH-pyrrole, hex-5-en-2-one, and methyl 2-methylpropanoate.
[0023] Provided is also a composition for use as an arthropod attractant that
includes: i) a cycloalkanone; and
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sf-3391325 Attorney Docket No. 677032000740 ii) optionally one or more compounds selected from compounds of
formulae (la), (Xb), (Xc), and (XIa), or any combination thereof
[0024] In some embodiments, the cycloalkanone is a C4 to C6 cycloalkanone. In
one embodiment, the cycloalkanone is cyclopentanone. In another embodiment, the
composition includes cyclopentanone and ethyl acetate.
[0025] Provided is also a composition for use as an arthropod attractant that
includes two or more compounds selected from Table A, Group I. In some
embodiments, the composition is used in an arthropod trap. In one embodiment, the
arthropod trap is suction-based, light-based, electric current-based, or any
combination thereof.
[0026] Provided is also a composition comprising a compound identified
according to any one of the methods described above.
DESCRIPTION OF THE FIGURES
[0027] The present application can be best understood by references to the
following description taken in conjunction with the accompanying figures.
[0028] FIG. la is schematic of the maxillary palp capitate peg sensillum with
three ORNs.
[0029] FIG. lb depicts representative traces and mean change in firing rate of the
Aedes aegypti cpA (large amplitude that expresses Grl, Gr2 and Gr3) neuron to a
0.5-s human skin odor stimuli from glass beads laden with foot odor, in which
responses to clean-bead controls from the same recording session have been
subtracted, and n = 6-7.
[0030] FIG. lc includes a bar graph (left) summarizing the cpA response for
individual components of skin odor in A. aegypti and A. gambiae, and representative
traces and mean increase in firing rate of the cpA neuron to 0.5-s pulses of individual components of skin odor in A. aegypti and A. gambiae, where n = 4-7 (right).
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sf-3391325 Attorney Docket No. 677032000740
[0031] FIG. Id is a graph illustrating the temporal response of the A. aegypti cpA mean firing frequency to a 1-s stimulus counted in 100-ms bins, where average
response to n = 4-5 stimuli is repeated in 15 s cycles.
[0032] FIG. le is a graph illustrating A. aegypti cpA responses to representative
activating odorants are dose dependent, in which all odorants except C02 is dissolved in paraffin oil (PO) at 10~2 except where indicated, and error bars are s.e.m.
[0033] FIG. 2a is a comparison of chemical structures of butyraldehyde, butyric
acid, and butyryl chloride.
[0034] FIG. 2b depicts representative cp responses to 0.5-s pulses of indicated
odorants after a 3-min pre-exposure to butyryl chloride (10~2) (cpA-off) or solvent
(sham treatment).
[0035] FIG. 2c is a bar graph illustrating the mean odorant-evoked responses of
the cpA neuron in cpA-off and sham treated mosquitoes, and FIG. 2d is a bar graph
illustrating the combined odor-evoked responses of two neighbouring neurons, cpB
and cpC, where for both of these figures, n = 6 individuals, 1-4 sensilla surveyed per individual; analysed by nested ANOVA, and baseline refers to cpA activity in the
presence of room air.
[0036] FIG. 2e is a graph illustrating averaged traces and FIG. 2f is a graph
illustrating mean electroantennograph (EAG) responses to air puffed over glass beads laden with foot odor or a clean bead control, where EAG peaks are normalized to 3- methyl-l-butanol response, n = 9, and analysed by i-test.
[0037] FIG. 2g depicts sample traces and mean cpA responses to 0.5-s pulses of
foot odor (mixed beads from Person 1 and Person 2) in cpA-off and sham treated
mosquitoes, in which n = 4 individuals, 2-3 sensilla surveyed per individual, and
analysed by nested ANOVA.
[0038] FIG. 2h is a schematic of wind tunnel assay, where human odor was
provided by a dish of glass beads that had been worn in socks for ~6 hrs (Person 1),
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sf-3391325 Attorney Docket No. 677032000740 and flight behaviour of individual female mosquitoes was recorded for 5 min or until they landed on the beads.
[0039] FIGS. 2i-k are bar graphs illustrating the proportion of butyryl chloride
pre-exposed and sham treated mosquitoes presented with beads with no odor or foot
odor that landed on beads (FIG. 2i), that took off from the release cage (FIG. 2j), and that did take off that succeeded in landing on the beads (FIG. 2k), where n = 20-23
individuals per condition, analysed by one-tailed proportion Z-test, * p < 0.05, ** p <
0.01, *** p < 0.001, and error bars are s.e.m. All odorants except C02 were dissolved in paraffin oil at 10~2 except where indicated.
[0040] FIG. 3a is a schematic providing an overview of the cheminformatics
method used to identify novel cpA ligands from a large untested chemical space.
[0041] FIG. 3b depicts representative traces and mean responses of the A. aegypti cpA neuron to 0.5-s pulses of 138 predicted compounds screened using single- sensillum recordings, in which odorants were diluted to 10~2 in paraffin oil or water,
and responses to solvent have been subtracted, n = 2-6, and error bars are s.d.
[0042] FIG. 3c depicts representative traces and mean percent inhibition of the A.
aegypti cpA neuron's response to 0.15% C02 by a panel of 107 odorants presented as a 1-s stimulus (10~2) in the middle of a 3-s C02 stimulus, where n = 2, except for ethyl and methyl pyruvate, n = 6. Percent inhibition was calculated by comparing mean
odorant overlay responses to mean solvent overlay responses, and error bars are s.d.
[0043] FIG. 3d depicts representative traces from the A. aegypti cp sensillum to 1- s pulses of 0.15% C02 prior to and following a 3-s exposure to either solvent (paraffin oil) or (E)-2-methylbut-2-enal (10 1).
[0044] FIG. 3e is a graph illustrating the cpA baseline activity in the 1 s prior to
each stimulus is elevated following exposure to odorant, where error bars are s.e.m.
[0045] FIG. 3f is a bar graph illustrating the mean responses of the cpA neuron to
1-s pulses of 0.15% C02, calculated by subtracting the 1 s of the baseline activity
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sf-3391325 Attorney Docket No. 677032000740 prior to each stimulus, where n = 5-6 individuals, analysed by i-test, *** p < 0.001,
and error bars are s.e.m.
[0046] FIG. 4a is a graph illustrating the dose response of inhibition of A. aegypti cpA neuron when a 1-s stimulus of ethyl pyruvate is overlaid on a 3-s stimulus of
0.15% C02, where n = 6 for each concentration.
[0047] FIG. 4b depicts representative trace and mean response when a 1-s
stimulus of ethyl pyruvate (10~2) is overlaid on a 2-s stimulus of foot odor (mixed
beads from Person 1 and Person 2), where n = 6.
[0048] FIG. 4c depicts representative images (left) of hand-in-cage assay mesh
window and a graph (right) illustrating the mean number of mosquitoes on the netting at the indicated time points for ethyl pyruvate-treated or solvent-treated netting, n = 8 each.
[0049] FIG. 4d is a graph illustrating the dose responses of the cpA neuron to
cyclopentanone in A. aegypti and C. quinquefasciatus, where n = 5-6.
[0050] FIG. 4e is a graph illustrating the mean responses in 100 ms bins to pulses of cyclopentanone (10~2), C02, or blank odor cartridges, n = 4 replicates of 6 repeated pulses of each odorant.
[0051] FIG. 4f depicts representative traces of repeated 1-s stimuli of
cyclopentanone (10~2) and 0.15% C02.
[0052] FIG. 4g is a schematic of two-choice greenhouse experiments with two
counterflow geometry traps, in which mosquitoes were trapped overnight in odorant- baited and solvent (water)-baited traps.
[0053] FIG. 4h is a graph illustrating the mean number of mosquitoes/trial
captured in baited and control traps, n = 9 trials with C02, n = 6 with each
concentration of cyclopentanone.
[0054] FIG. 4i is a graph illustrating the preference index for C02 and
cyclopentanone trials (from FIG. 4h), and for similar two-choice assays between
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sf-3391325 Attorney Docket No. 677032000740 lactic acid and solvent (n = 6) or between C02 and C02 with ethyl pyruvate, n = 5,
where error bars are s.e.m, i-test, * p < 0.05, ** p < 0.01, *** p < 0.001.
[0055] FIG. 5a is a graph illustrating the principle component analysis (PCA) of
odorants calculated from 64 optimized molecular descriptor values, in which circle
size corresponds to cpA activity evoked by each odorant, and dark green = human
skin odorants, light green = predicted activator, red = predicted inhibitor, grey =
predicted odorants that are inactive, black = odorants that activate A. gambiae
olfactory receptors (AgOrs).
[0056] FIG. 5b illustrates the PCA analysis of FIG. 5a relabelled by chemical
functional groups, with circle size representing their cpA activity (right).
[0057] FIG. 5c is a hierarchical clustering of odorants that interact with cpA with inter-chemical distances generated from activity-optimized descriptors, and sample
structures and associated activity are provided..
[0058] FIG. 5d provides an overview of the support vector machine (SVM)
integrated pipeline to improve computational prediction of novel CpA ligands.
[0059] FIG. 5e is a graph illustrating the receiver-operating-characteristic curve
(ROC) showing increased predictive accuracy of SVM method (red line) to our
previous non-SVM method (black line) using a 5-fold cross-validation.
[0060] FIG. 5f is a bar graph illustrating the mean responses of the A. aegypti cpA neuron to 0.5-s pulses of 22 newly predicted compounds screened as in FIG. 3b,
where salmon bars correspond to odorants found in human odor, odorants were
diluted to 10"2 in paraffin oil or water, and responses to solvent have been subtracted, and n = 2-5.
[0061] FIG. 6 is an exemplary model for cpA-mediated host-seeking and odorants that disrupt it, in which inhibitors may be used to block attraction to both C02 and
skin odor (MASK) and activators may be used as lures for traps (PULL).
[0062] FIG. 7a is a schematic of a human odor delivery system.
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sf-3391325 Attorney Docket No. 677032000740
[0063] FIG. 7b is a schematic of an activation screen. For the activation screen,
insertion sites for "blank" and "odor cartridges" were spaced 12 cm apart, and flow
rates through the stimulus controller were adjusted for each individual preparation.
Black arrows indicate switch in airflow during stimulus delivery.
[0064] FIGS. 8a-8f illustrate an electrophysiological analysis of cpA action
potential and spiking activity in response to various stimuli (such as odors).
[0065] FIG. 9a illustrates sample traces from repeated stimulus experiments: 1-s
pulses of odorant (10-2 in PO except C02) were repeated every 15 s; temporal
dynamics of responses to each pulse of the same odorant were virtually identical and are summarized in FIG. Id.
[0066] FIG. 9b illustrates sample traces and mean cpA responses to 0.5-s pulses
of 0.15% and 0.4% C02 from cpA-off or sham treated mosquitoes 6, 12, and 24 hours after treatment.
[0067] FIG. 9c illustrates averaged traces of EAG responses to 0.5-s stimuli of
indicated odorants (10-1 in PO).
[0068] FIG. 9d illustrates EAG responses normalized to the reference odor 3- methyl-l-butanol. No significant differences due to treatment (n = 9; t-test).
[0069] FIG. 9e is a schematic of the apparatus used to assay short-range attraction to heat and humidity.
[0070] FIG. 9f illustrates mosquitoes' tendency to rest at the top surface of the
cage increased in the presence of a warm, wet stimulus. Mosquitoes in each treatment group were observed to probe through the mesh with their proboscides when stimulus was present. No significant differences due to treatment (n = 6 replicates; Mann- Whitney rank-sum test).
[0071] FIG. 10a is a schematic of the wind tunnel used in the wind tunnel assays showing the mosquito release chamber, human foot odor bead stage, and retracted
bead cover.
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sf-3391325 Attorney Docket No. 677032000740
[0072] FIG. 10b shows histograms quantifying the number of mosquitoes that
took off during the 5-minute assay in each of three experimental conditions. Heights
of bars are proportional across all three histograms. X's mark when a mosquito
landed on the odor source.
[0073] FIG. 10c shows plots where each row indicates flight behavior of each
individual mosquito assayed. Shaded areas on each line represent time between when the mosquito left the release cage and when it landed on the beads or the assay ended at 5 min. Colors correspond to where the mosquito was located in the wind tunnel (as indicated in FIG. 10a) at each moment.
[0074] FIG. 11a illustrates the mean percent inhibition of A. aegypti cpA response to 0.15% C02 overlaid with different concentrations of methyl pyruvate (n = 6).
[0075] FIG. l ib illustrates the mean responses of the cpA neuron to different
concentrations of thiophene for C. quinquefasciatus and A. aegypti (n = 4).
[0076] FIG. 11c illustrates that the temporal response profiles elicited by repeated exposures to cyclopentanone are similar to those elicited by C02. Individuals were
exposed to 6 repeated 1-s pulses of either 0.15% C02 or cyclopentanone (10-2),
spaced 20 s apart. Shown are the mean responses (across 4 animals per treatment) for each sequential pulse. Activity was calculated in 100 ms bins for a total of 6 s
following the onset of the stimulus. Values were adjusted by subtracting baseline
activity measured 5-6 s after each pulse.
DETAILED DESCRIPTION
[0077] The following description is presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific
materials, techniques, and applications are provided only as examples. Various
modifications to the examples described herein will be readily apparent to those of
ordinary skill in the art, and the general principles defined herein may be applied to
other examples and applications without departing from the spirit and scope of the
various embodiments. Thus, the various embodiments are not intended to be limited
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sf-3391325 Attorney Docket No. 677032000740 to the examples described herein and shown, but are to be accorded the scope
consistent with the claims.
Screening Methods
[0078] Provided herein are screening methods for identifying one or more
compounds that are repellents for at least one arthropod species. The repellants may
mask or inhibit detection of human skin odor by at least one arthropod species.
Provided herein are also screening methods for identifying one or more compounds
that are attractants for at least one arthropod species.
[0079] Arthropods are invertebrate animals characterized as having an
exoskeleton, a segmented body, and jointed appendages. Arthropods belong to the
Phylum Arthropoda under Kingdom Animalia. The Phylum of Arthropoda, or an
"arthropod" includes any invertebrate animal from the Classes of Insecta, Arachnida,
Diplopoda, Chilopoda, Crustacea, and Xiphosura. In some embodiments, arthropod
may refer to insects and arachnids that are exoparasitic sanguinivorous feeding pests, including any insect from the Order Diptera, such as mosquitoes, and any arachnid
from the Order Ixodida, such as ticks. Examples of mosquitoes include Anopheles,
Mimomyia, Culiseta, Orthopodomyia, Mansonia, Culex, Heizmannia, Aedes,
Armigeres, Uranotaenia, Tripteroides, Topomyia, Malaya, and Toxorhynchite. As a
specific type of such mosquito, an example of the Anopheles includes anopheles
sinesis Wiedemann. Examples of the Culex include Culex quinquefasciatus, Culex
pipiens pallens, Culex pipiens molestus, and Culex tritaeniorhynchus. Examples of
the Aedes include Aedes albopictus and Aedes aegypti. An example of the Armigeres includes Armigeres subalbatus.
[0080] The screening methods can be used to identify one or more arthropod
repellents based on masking or inhibiting the detection of the skin odor by a Grl-,
Gr2- and/or Gr3-expressing_neuron (e.g. , that may be a cpA neuron). In some
embodiments, the method includes: a) providing a candidate compound and a skin
odor; b) providing a sample comprising a Grl-, Gr2- and/or GrJ-expressing neuron;
c) contacting the candidate compound with the sample; d) measuring the detection of
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sf-3391325 Attorney Docket No. 677032000740 the skin odor by the Grl-, Gr2- and/or Gr 3-expressing_neuron; e) comparing the
detection of the skin odor by the Grl-, Gr2- and/or Gr3-expressing_neuron after
contact with the candidate compound to the detection of the skin odor by the Grl-,
Gr2- and/or Gr3-expressing_neuron in the absence of the candidate compound; and f) identifying a compound that is a repellent for at least one arthropod species by
determining whether or not the candidate compound masks or inhibits the detection of the skin odor by the Grl-, Gr2- and/or Gr 3-expressing_neuron.
[0081] The screening methods can also be used to identify one or more arthropod attractants based on activating a Grl-, Gr2- and/or Gr 3-expressing_neuron.
Candidate Compounds
[0082] The screening methods provided herein may be used to screen one
candidate compound or a plurality of candidate compounds. The one or more
candidate compounds may be natural or synthetic compounds. For example, the one or more candidate compounds may be from bacterial, fungal, plant and animal
extracts that are commercially available or readily produced. The one or more
candidate compounds can also be chemically-modified compounds, such as by
acylation, alkylation, esterification, or acidification of natural compounds. The one or more candidates compounds screened in the methods described herein may be preselected based on one or more criteria. For example, a set of compounds with
structural similarities to known insect repellents, like DEET, may be screened and
selected for use in the methods described herein. A computation method may be used to select such candidate compounds. Other criteria used for selecting the one or more candidate compounds include the environmental impact of the compounds, regulatory approval of the compounds for human consumption (e.g. , FDA- approval), and the
smell of the compounds (e.g. , natural fragrances, aromas, or odors).
Skin Odor
[0083] The skin odor provided with a candidate compound or plurality of
candidate compounds, may be an individual odor or a blend of odors. One of skill in the art would recognize that vertebrate odor (e.g. , human odor) is a blend of hundreds
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sf-3391325 Attorney Docket No. 677032000740 of volatile chemicals from skin, sweat, and associated microbiota. Odors that can be found in human skin and that activates the Grl-, Gr2- and/or Gr J-expressing_neuron
may include, for example, the compounds in FIG. 1A or any combinations thereof.
Vertebrate odor may also include skin odor blend collected from placing an adsorbent or absorbent material in contact with skin, or placed in the headspace above the skin, or a gas passed over the skin, Or skin brought into close vicinity of the cpA.
Grl-, Grl- and/or Gr 3 -Expressing Neuron
[0084] The sample provided in the methods described herein may include a Grl-,
Gr2- and/or Gr3-expressing_neuron. The neuron may include three conserved seven- transmembrane domain proteins encoded by members of the gustatory receptor (Gr)
gene family (Grl, Gr2, and/or Gr3 in most mosquitoes, or AgGr22, AgGr23, and
AgGr24 in A. gambiae (FIG. la)). Such neuron may be a cpA neuron, which is an
olfactory receptor neuron (ORN), housed in specialized capitate peg (cp) sensilla and express the C02 receptor. In mosquitos (Aedes aegypti), cpA neurons are located in
the maxillary palp organs. However, the location of cpA neurons in other arthropod
species may vary. The neuron may be activated in response to a vertebrate skin odor.
In one embodiment, the sample includes a cell expressing Grl, Gr2, Gr3, or a
combination thereof.
Grl Polynucleotides and Polypeptides
[0085] In some embodiments, the neurons of the present disclosure may include a
Grl receptor. Grl receptors are known in the art. The Grl receptors of the present
disclosure may include a Grl receptor selected from, for example, Aedes aegypti,
Anopheles gambiae, Culex quinquefasciatus, Bombyx mori, Tribolium castenium,
Phlebotomus papatasi, Heliconius melpomene, Manduca sexta, and Mayetiola
destructor.
[0086] A homolog or an ortholog or any known or putative Grl receptor may also be used in the methods and systems described herein. A homolog may be a protein
whose nucleic acid sequence that encodes that protein has a similar sequence to the
nucleic acid sequence that encodes a known or putative Grl receptor, or a protein
18
sf-3391325 Attorney Docket No. 677032000740 whose amino acid sequence is similar to the amino acid sequence of a known or
putative Grl receptor. Grl homologs may have functional, structural or genomic
similarities to any known or putative Grl receptor. One of skill in the art would
recognize the techniques that may be employed to clone homologs of a gene, using
genetic probes and PCR. Homologs can also be identified by reference to various
databases and identity of cloned sequences as homolog can be confirmed using
functional assays and/or by genomic mapping of the genes. Additionally, one of skill in the art would understand that an ortholog is an evolutionarily-related polypeptide or polynucleotide sequence in different species that have similar sequences and
functions, and that develop through a speciation event.
[0087] In some embodiments, a homolog and/or ortholog of a Grl receptor is a
protein whose nucleic acid sequences have at least 30%, 40%, 50%, 60%, 65%, 70%,
75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the nucleic acid sequence encoding any known or putative Grl receptor. In another embodiment, a homolog of a Grl receptor is a protein whose amino acid sequence has at least 30%, 40%, 50% 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%,
94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence encoding any known or putative Grl receptor.
[0088] The Grl receptor may be from one or more arthropod species. For
example, in certain embodiments, the Grl receptor is a homolog or ortholog of the
Grl receptor from Aedes aegypti. In some embodiments, the Grl receptor has at least
50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,
97%, 98%, or 99% sequence identity to a polypeptide encoding a Grl receptor from
Aedes aegypti.
[0089] One of skill in the art would recognize the methods and techniques that
may be employed to determine the percent identity between two amino acid
sequences, or between two nucleic acid sequences. One of skill in the art would also recognize that the sequences can be aligned for optimal comparison purposes. For
example, gaps can be introduced in one or both of a first and a second amino acid or
nucleic acid sequence for optimal alignment and non-homologous sequences can be
19
sf-3391325 Attorney Docket No. 677032000740 disregarded for comparison purposes). The amino acid residues or nucleotides at
corresponding amino acid positions or nucleotide positions can then be compared.
Methods of comparing nucleic acid or amino acid sequences are well-known in the
art.
Gr2 Polynucleotides and Polypeptides
[0090] In some embodiments, the neurons of the present disclosure may include a
Gr2 receptor. Gr2 receptors are known in the art. The Gr2 receptors of the present
disclosure may include a Gr2 receptor selected from, for example, Aedes aegypti,
Anopheles gambiae, Culex quinquefasciatus, Bombyx mori, Tribolium castenium,
Phlebotomus papatasi, Heliconius melpomene, Manduca sexta, and Mayetiola
destructor.
[0091] A homolog or an ortholog or any known or putative Gr2 receptor may also be used in the methods and systems described herein. A homolog may be a protein
whose nucleic acid sequence that encodes that protein has a similar sequence to the
nucleic acid sequence that encodes a known or putative Gr2 receptor, or a protein
whose amino acid sequence is similar to the amino acid sequence of a known or
putative Gr2 receptor. Gr2 homologs may have functional, structural or genomic
similarities to any known or putative Gr2 receptor.
[0092] In some embodiments, a homolog and/or ortholog of a Gr2 receptor is a
protein whose nucleic acid sequences have at least 30%, 40%, 50% 60%, 65%, 70%,
75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the nucleic acid sequence encoding any known or putative Gr2 receptor. In another embodiment, a homolog of a Gr2 receptor is a protein whose amino acid sequence has at least 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%,
94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence encoding any known or putative Gr2 receptor.
[0093] The Gr2 receptor may be from one or more arthropod species. For
example, in certain embodiments, the Gr2 receptor is a homolog or ortholog of the
Gr2 receptor from Aedes aegypti. In some embodiments, the Gr2 receptor has at least
20
sf-3391325 Attorney Docket No. 677032000740
50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,
97%, 98%, or 99% sequence identity to a polypeptide encoding a Gr2 receptor from
Aedes aegypti.
Gr3 Polynucleotides and Polypeptides
[0094] In some embodiments, the neurons of the present disclosure may include a
Gr3 receptor. Gr3 receptors are known in the art. The Gr3 receptors of the present
disclosure may include a Gr3 receptor selected from, for example, Aedes aegypti,
Anopheles gambiae, Culex quinquefasciatus, Bombyx mori, Tribolium castenium,
Phlebotomus papatasi, Heliconius melpomene, Manduca sexta, and Mayetiola
destructor.
[0095] A homolog or an ortholog or any known or putative Gr3 receptor may also be used in the methods and systems described herein. A homolog may be a protein
whose nucleic acid sequence that encodes that protein has a similar sequence to the
nucleic acid sequence that encodes a known or putative Gr3 receptor, or a protein
whose amino acid sequence is similar to the amino acid sequence of a known or
putative Gr3 receptor. Gr3 homologs may have functional, structural or genomic
similarities to any known or putative Gr3 receptor.
[0096] In some embodiments, a homolog and/or ortholog of a Gr3 receptor is a
protein whose nucleic acid sequences have at least 30%, 40%, 50% 60%, 65%, 70%,
75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the nucleic acid sequence encoding any known or putative Gr3 receptor. In another embodiment, a homolog of a Gr3 receptor is a protein whose amino acid sequence has at least 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%,
94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence encoding any known or putative Gr3 receptor.
[0097] The Gr3 receptor may be from one or more arthropod species. For
example, in certain embodiments, the Gr3 receptor is a homolog or ortholog of the
Gr3 receptor from Aedes aegypti. In some embodiments, the Gr3 receptor has at least
50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,
21
sf-3391325 Attorney Docket No. 677032000740
97%, 98%, or 99% sequence identity to a polypeptide encoding a Gr3 receptor from
Aedes aegypti.
Measuring the Detection of Skin Odor
[0098] The detection of the skin odor by a Grl-, Gr2- and/or Gr3-expressing
neuron may be measured by any suitable methods and techniques known in the art.
Suitable methods and techniques include, for example, measuring
electrophysiological parameters. One of skill in the art would recognize that whole
organ recordings known as electroantennograms (EAGs) and electropalpograms
(EPGs) can be used to detect the aggregate electrical activities from a large number of neurons in response to odors. Another method of detecting skin odor activation is
using imaging of neural activity using fluorescent or luminescent reporters of
calcium, pH, voltage, and synaptic release.
Identifying Arthropod Repellents
[0099] The detection of the skin odor by a Grl-, Gr2- and/or Gr3-expressing
neuron after contact with the candidate compound or plurality of candidate
compounds is compared with the detection of the skin odor by a Grl-, Gr2- and/or
Gr3-expressing_neuron in the absence of the candidate compound or plurality of
candidate compounds to determine whether a candidate compound is an arthropod
repellent.
[00100] In some embodiments, a candidate compound is selected as an arthropod
repellent based on the ability of the candidate compound to mask the detection of the skin odor by a Grl-, Gr2- and/or GrJ-expressing neuron. In certain embodiments, a
candidate compound is selected as an arthropod repellent based on at least 75%, 80%,
85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% masking of the
detection of the skin odor by a Grl-, Gr2- and/or GrJ-expressing_neuron.
[00101] In other embodiments, a candidate compound is selected as an arthropod
repellent based on the ability of the candidate compound to inhibit the detection of the skin odor by the Grl-, Gr2- and/or Gr3-expressing_neuron. In certain embodiments, a
22
sf-3391325 Attorney Docket No. 677032000740 candidate compound is selected as an arthropod repellent based on at least 75%, 80%,
85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% inhibition of the
detection of the skin odor by the Grl-, Gr2- and/or Gr3-expressing_neuron.
Identifying Arthropod Attractants
[00102] One or more candidate compounds may be identified as an arthropod
attractant based on the activation of the Grl-, Gr2- and/or Gr 3-expressing_neuron. In certain embodiments, a candidate compound is selected as an arthropod attractant
based on at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% increase in activation of the Grl-, Gr2- and/or Gr 3-expressing_neuron over
baseline activity in standard room air.
Screening Systems
[00103] Provided herein are also systems used for identifying one or more
compounds that are repellents for at least one arthropod species, based on masking or inhibiting the detection of human skin odor by at least one arthropod species.
[00104] In some embodiments, the system includes: a) a sample that includes a
Grl-, Gr2- and/or Gr J-expressing_neuron; b) a skin odor; and c) one or more
compounds that each is a repellent for at least one arthropod species, wherein the one or more compounds each masks or inhibits the detection of the skin odor by the Grl-,
Gr2- and/or Gr3-expressing_neuron. In certain embodiments, the one or more
compounds each masks or inhibits at least 75%, 80%, 85%, 90%, 91%, 92%, 93%,
94%, 95%, 96%, 97%, 98% or 99% of the detection of the skin odor by the Grl-,
Gr2- and/or Gr3-expressing_neuron.
[00105] As described above, the skin odor may be an individual odor or the skin
odor may be made up of a plurality of odors. In some embodiments, the Grl-, Gr2- and/or Gr3-expressing_neuron may be from an arthropod or, in certain embodiments, an insect.
[00106] Provided herein are also systems used for identifying one or more
compounds that are attractants for at least one arthropod species, based activation of
23
sf-3391325 Attorney Docket No. 677032000740 the Grl-, Grl- and/or Gr3-expressing_neuron. In certain embodiments, a candidate
compound is selected as an arthropod attractant based on at least 75%, 80%, 85%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% activation of the Grl-,
Gr2- and/or Gr3-expressing_neuron.
Compounds Identified and Compositions Thereof
[00107] The following compounds have been identified using the methods and
systems described herein to modulate an arthropod olfactory neuron, such as a Grl-,
Gr2- and/or Gr3-expressing neuron. One or more of such compounds may be used in a composition that is an arthropod repellent.
[00108] In some embodiments, the compound has a structure of formula (I):
Figure imgf000026_0001
wherein:
X1 and X2 are each independently selected from the group consisting of O, S
and NH;
R1 and R2 are each independently selected from the group consisting of H, D, halide, optionally substituted aliphatic group, and optionally substituted hetero- aliphatic group; or R1 and R2 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
[00109] In some embodiments of formula (I), when X1 and X2 are each O, and R1 or R2 is methyl, then the other R2 or R1 is H, D, halide, optionally substituted C2+
aliphatic group, and optionally substituted hetero-aliphatic group. In certain
embodiments of formula (I), when X1 and X2 are each O, R1 and R2 are each other
than methyl (i.e., the compound of formula (I) is other than methyl acetate).
[00110] In certain embodiments, aliphatic compounds include any non-aromatic
compounds, and may be saturated or unsaturated with one or more double or triple
24
sf-3391325 Attorney Docket No. 677032000740 bonds. Examples of aliphatic compounds include (Ci to Cis)alkyls, (Ci to C15)
alkenyls, (Ci to Cis)alkynyls, cycloalkyls, cycloalkenyls, and cycloalkynyls. In
certain embodiments, hetero-aliphatic groups include any aliphatic compounds in
which at least one carbon atom is replaced by a heteroatom, such as nitrogen, oxygen or sulfur. Examples of hetero-aliphatic groups may include (Ci to Ci4)hetero-alkyls,
(Ci to Ci4)hetero- alkenyls, and (Ci to Ci4)hetero-alkynyls.
[00111] Optionally substituted groups which contain halogens may include, for
example, haloalkanes, and haloalkenes. Optionally substituted groups which contain oxygen may include, for example, hydroxyls, carbonyls, aldehydes, haloformyls,
carbonate esters, carboxylates, carboxyls, esters, ethers, peroxides, hydroperoxides,
hemiacetals, hemiketals, acetals, ketals, orthoesters, and orthocarbonate esters.
Optionally substituted groups which contain nitrogen may include, for example,
amides, amines, imines, enamines, imides, azides, azo compounds, cyanates, nitrates, nitros, nitriles, nitrosos, and pyridyls. Optionally substituted groups which contain
sulfur may include, for example, thiols, sulfides, disulfides, sulfoxides, sulfones,
sulfinos, sulfos, thiocyanates, thiones, and thials. Optionally substituted groups which contain phosphorus may include, for example, phosphinos, phosphonos, and
phosphates; optionally substituted groups which contain boron, such as boronos,
boronates, borinos, and borinates. Optionally substituted groups which contain
silicon may include, for example, silyl ethers, silicates, siloxanes, and silanes.
[00112] In one embodiment, the compound has a structure of formula (la):
Figure imgf000027_0001
wherein:
R1 and R2 are each independently selected from the group consisting H, OH,
SH, an optionally substituted aliphatic or hetero-aliphatic group having 1 to 6 carbon atoms, and a cyclic group having 4 to 8 ring carbon atoms; or R1 and R2 can be linked
25
sf-3391325 Attorney Docket No. 677032000740 together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or
heteroaromatic ring system having 3 to 6 ring carbon atoms.
[00113] The aliphatic or hetero-aliphatic groups may be straight or branched, and
saturated or unsaturated.
[00114] In some embodiments of formula (la), when R1 or R2 is methyl, then the
other R2 or R1 is H, D, halide, optionally substituted C2+ aliphatic group, and
optionally substituted hetero-aliphatic group. In certain embodiments of formula (la), when R1 and R2 are each other than methyl (i. e. , the compound of formula (la) is
other than methyl acetate).
[00115] In some embodiments of formula (la), R1 and R2 are each independently
selected from the group consisting of H, OH, SH, an optionally substituted aliphatic
or hetero-aliphatic group having 1 to 4 carbon atoms; or R1 and R2 can be linked
together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or
heteroaromatic ring system having 4 to 6 ring carbon atoms.
[00116] In other embodiments of formula (la), when X1 and X2 are each O, and R2 is an optionally substituted aliphatic group, then R1 is H, OH, SH, an optionally
substituted aliphatic or hetero-aliphatic group having 1 to 6 carbon atoms. In certain
embodiments of formula (la), when X1 and X2 are each O, R2 is an optionally
substituted aliphatic group, and R1 is a cyclic group having 4 to 8 ring carbon atoms, then the cyclic group is other than optionally substituted aryl. In certain embodiments of formula (la), when X1 and X2 are each O, R2 is an optionally substituted aliphatic
group, and R2 is a cyclic group having 4 to 8 ring carbon atoms, then the cyclic group is other than aryl substituted with an optionally substituted amino group.
[00117] In another embodiment, the compound has a structure of formula (lb):
26
sf-3391325 Attorney Docket No. 677032000740 wherein:
R1 and R2 are each independently selected from the group comprising H, OH,
SH, an optionally substituted aliphatic or hetero-aliphatic group having 1 to 6 carbon atoms, and a cyclic group having 4 to 8 ring carbon atoms; or R1 and R2 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or
heteroaromatic ring system having 3 to 6 ring carbon atoms.
[00118] In some embodiments of formula (lb), R1 and R2 are each independently
selected from the group consisting of H, OH, SH, and an optionally substituted
aliphatic or hetero-aliphatic group having 1 to 4 carbon atoms; or R1 and R2 can be
linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
[00119] In one embodiment, the compound of formula (I) is selected from methyl propanoate, methyl 2-methylpropanoate, propyl acetate, ethyl acetate, propyl formate, prop-2-enyl-propanoate, 2-methylpropyl formate, methyl butanoate, methyl acetate,
methyl propionate, propyl formate, isobutyl formate, methyl isobutyrate, methyl
butyrate, ethyl formate, methyl methacrylate, alpha-angelica lactone, allyl propionate, allyl butyrate, dimethyl carbonate, methyl 2-methylprop-2-enoate, ethyl formate, ethyl
(E)-but-2-enoate, prop-2-enyl-butanoate, oxolan-2-ylmethyl acetate, benzyl formate, propan-2-yl benzoate, 2-phenylethyl 3-methylbutanoate, [(E)-3-phenylprop-2-enyl]
formate, 2-phenylethyl (E)-2-methylbut-2-enoate, 2-(trimethylazaniumyl)acetate, oct- l-en-3-yl butanoate, 2-phenylethyl propanoate, benzyl 3-oxobutanoate, [(2E)-3,7- dimethylocta-2,6-dienyl] formate, 2-methylpropyl-(Z)-but-2-enoate, 2-phenylethyl
butanoate, ethyl pyruvate, and methyl pyruvate.
[00120] In another embodiment, the compound of formula (I) is selected from 2,2- dimethyl-3-(2-methyl-propenyl)-cyclopropanecarboxylic acid ethyl ester, acetic acid
2,2,6-trimethyl-6-vinyl-tetrahydro-pyran-4-yl ester, isobutyric acid l-methyl-l-(4- methyl-cyclohex-3-enyl)ethyl ester, acetic acid 2-isopropylidene-4,8-dimethyl- l,2,3,3a,4,5,6,8a-octahydro-azulen-6-yl ester, (4-ieri-butyl-phenyl)-acetic acid methyl ester, acetic acid l-[2-(3,3-dimethyl-oxiranyl)-ethyl]-l-methyl-allyl ester, pentanoic
acid 5,5,6-trimethyl-bicyclo[2.2.1]hept-2-yl ester, (lH-indol-2-yl)acetic acid, 6-
27
sf-3391325 Attorney Docket No. 677032000740 methyl-2-(3-methyl-cyclohex-3-enyl)-hept-5-en-2-ol, propionic acid 5-isopropenyl-2- methyl-cyclohex-2-enyl ester, 2-hydroxymethyl-but-2-enoic acid 7-(2-methyl-but-2- enoyloxy)-5-,6,7,7a-tetrahydro-3H-pyrrolizin-l-ylmethyl ester, (2-isopropenyl-l- methyl-cyclobutyl)-acetic acid, 7,8-dimethyl-8-aza-bicyclo[3.2. l]octane-2-carboxylic acid methyl ester, acetic acid 2,6,10,10-tetramethyl-l-oxa-spiro[4.5]dec-6-yl ester,
isobutyric acid 6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2ylmethyl ester, 4-hydroxy-3,7- dimethyl-octahydro-chromen-2-one, 4,8-dimethyl-octahydro-chromen-2-one, 2- methyl-butyric acid 6,6-dimethyl- bicyclo[3.1.1]hept-2-en-2-ylmethyl ester, l-(3,8- dimethyl-1,2, 3,4,5, 6,7,8-octahydro-azulen-5-yl)-l-methyl-ethyl ester acetic acid, 2- hydroxy-2-(l-methoxy-ethyl)-3-methyl-butyric acid 7-hydroxy-5,6,7,7a-tetrahydro- 3H-pyrrolizin-l-ylmethyl ester, carbamic acid ethyl ester, 2-amino-5-guanidino- pentanoic acid, 2-amino-succinamic acid, 2-hydroxy-2-(l-hydroxy-ethyl)-3-methyl- butyric acid 7-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-l-ylmethyl ester, 4- ethylidene-7-hydroxy-6,7,14-trimethyl-2,9-dioxa-14-aza-bicyclo[9.5.1]heptadec-l l- ene-3,8,17-trione, 6-methoxy-3H-benzooxazol-2-one, 2-amino-3-phenyl-propionic
acid, phenylalanine, glutamine, mandelonitrile benzoate, 3-Hydroxymethyl-6-methyl- 3a,3b,7a,8-tetrahydro-lH-4-oxa-8a-aza-cyclopenta[a]inden-5-one, methyl N- acetylisoleucinate, tryptophan, 2-amino-3-(3,4-dihydroxy-phenyl)-propionic acid, and
N-(tert-butyl)-4-methylbenzamide.
[00121] In other embodiments, the compound has a structure of formula (II):
Figure imgf000030_0001
wherein:
X3 and X4 are each independently selected from the group consisting O, S and
ΝΗ;
28
sf-3391325 Attorney Docket No. 677032000740
R3 and R4 are each independently selected from the group consisting of H, D, a halide, and optionally substituted aliphatic groups, or R3 and R4 can be linked
together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
[00122] In one embodiment, the compound has a structure of formula (Ila):
Figure imgf000031_0001
wherein:
R3 and R4 are each independently selected from the group consisting of H,
OH, SH, and an optionally substituted aliphatic or he tero- aliphatic group having 1 to
4 carbon atoms; or R3 and R4 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
[00123] In one embodiment, the compound of formula (II) is selected from 3- methylcyclopentane- 1 ,2-dione, 3 ,4-dimethylcyclopentane- 1 ,2-dione, 2-oxopentanoic acid, and 2-oxopropanal.
[00124] In other embodiments, the compound has a structure of formula (III):
Figure imgf000031_0002
wherein:
29
sf-3391325 Attorney Docket No. 677032000740
R5 and R6 are each independently selected from the group consisting of H, D, a halide, and optionally substituted aliphatic group; and
R7 is selected from the group consisting of an optionally substituted aliphatic
group; or
R5 and R6 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; or
R6 and R7 can be linked together to form an optionally substituted ring
selected from the group consisting of cycloalkenyl, aryl, and heterocycle.
5 7
[00125] In some embodiments of formula (III), R -R are each independently
selected from the group consisting of H, OH, SH, and an optionally substituted
aliphatic or hetero-aliphatic group having 1 to 4 carbon atoms. In other embodiment of formula (III), R5 and R6 can be linked together to form an optionally substituted
aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring
carbon atoms. In yet other embodiments of formula (III), R6 and R7 can be linked
together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or
heteroaromatic ring system having 4 to 6 ring carbon atoms.
[00126] In one embodiment, the compound of formula (III) is selected from
propan-2-yl benzoate, 2-phenylethyl (E)-2-methylbut-2-enoate, 4-ethylbenzaldehyde,
(E)-2-methylbut-2-enoic acid, 1-phenylbutan-l-one, (E)-2-methylbut-2-enoic acid, 1- phenylbutan-l-one, 3-methylbut-2-enoic acid, (E)-but-2-enoic acid, 2-methylpropyl- (Z)-but-2-enoate,(E)-pent-2-enal, 3-methylcyclopent-2-en-l-one, methyl 2- methylprop-2-enoate, (2E)-3,7-dimethylocta-2,6-dienoic acid, l-(lH-pyrrol-2- yl)ethanone, and ethyl (E)-but-2-enoate.
[00127] In another embodiment, the compound of formula (III) is selected from
N,N-diethyl-4-methyl-benzamide, N-butyl-3-fluoro-benzamide, N-(3-methyl-butyl)- benzamide, N-(tert-butyl)-4-methylbenzamide, 2-carbamoyl-benzoic acid anion, 3- hydroxymethyl-6-methyl-3a,3b,7a,8-tetrahydro-lH-4-oxa-8a-aza-cyclopenta[a]inden- 5-one, mandelonitrile benzoate, 7,8-dihydro-l-biopterin, N-(2-formyl-phenyl)- formamide, indolo[2,l-b]quinazoline-6,12-dione, 4-ethylidene-7-hydroxy-6,7,14- trimethyl-2,9-dioxa-14-aza-bicyclo[9.5.1]heptadec-l l-ene-3,8,17-trione, [hydroxy-(4-
30
sf-3391325 Attorney Docket No. 677032000740 hydroxy-quinolin-2-yl)-methylene]-methyl-oxonium, l-(2,6,6-trimethyl-cyclohex-2- enyl)-hepta-l,6-dien-3-one, 4-(l-hydroxy-4,7-dimethyl-l,4a,5,6,7,7a-hexahydro- cyclopenta[c]pyran-3-yl)-but-3-en-2-one, 2-hydroxymethyl-but-2-enoic acid 7-(2- methyl-but-2-enoyloxy)-5,6,7,7a-tetrahydro-3H-pyrrolizin-l-ylmethyl ester, 4- (2,5,6,6-tetramethyl-cyclohex-2-enyl)-but-3-en-2-one, 3-methyl-4-(2,6,6-trimethyl- cyclohex-2-enyl)-but-3-en-2-one, 2-hydroxy-4,4,6-trimethyl-cyclohexa-2,5-dienone, l-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone, 10- isopropylidene-3,7-dimethyl-cyclodeca-3,7-dienone, 3,3,6-trimethyl-hepta-l,5-dien- 4-one, and 3,5,5-trimethyl-4-(3-oxo-but-l-enyl)-cyclohex-3-enone.
[00128] In other embodiments, the compound has a structure of formula (IV):
Figure imgf000033_0001
Wherein:
selected from the group consisting of OH, SH, and N¾
R8, R9 and R10 are each independently selected from the group consisting of H,
D, a halides, an optionally substituted aliphatic group; or R8 and R9 can be linked
together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
[00129] In one embodiment, the compound has a structure of formula (IVa):
Figure imgf000033_0002
31
sf-3391325 Attorney Docket No. 677032000740 wherein:
R8 and R9 are each independently selected from the group consisting of H,
OH, SH, or an optionally substituted aliphatic or hetero- aliphatic group having 1 to 4 carbon atoms; or R8 and R9 can be linked together to form an optionally substituted
aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring
carbon atoms.
[00130] In one embodiment, the compound of formula (IV) is selected from 4- hydroxy-2,3-dimethyl-2H-furan-5-one, 2-hydroxypropanoic acid, and 3- hydroxybutan-2-one.
[00131] In another embodiment, the compound of formula (IV) is selected from 4- ethylidene-7-hydroxy-6,7,14-trimethyl-2,9-dioxa-14-aza-bicyclo[9.5.1]heptadec-ll- ene-3,8,17-trione, 2-hydroxy-2-(l-hydroxy-ethyl)-3-methyl -butyric acid 7-hydroxy- 5,6,7,7a-tetrahydro-3H-pyrrolizin-l-ylmethyl ester, and 2-hydroxy-2-(l-methoxy- ethyl)-3-methyl-butyric acid 7-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-l-ylmethyl ester.
[00132] In yet other embodiments, the compound has a structure of formula (V):
Figure imgf000034_0001
wherein:
X6 is selected from the group consisting of O, S, and NH;
R11 and R12 are each independently selected from the group consisting of H,
D, a halides, and an optionally substituted aliphatic group; or R11 and R12 can be
linked together to form an optionally substituted cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, or heterocycle.
[00133] In certain embodiments, the compound has a structure of formula (Va):
32
sf-3391325 Attorney Docket No. 677032000740
Figure imgf000035_0001
wherein:
R11 and R12 are each independently selected from the group consisting of H,
OH, SH, and an optionally substituted aliphatic or he tero- aliphatic group having 1 to
4 carbon atoms; or R11 and R12 can be linked together to form an optionally
substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
[00134] In one embodiment, the compound of formula (V) is selected from ethyl 2- oxopropanoate, methyl 2-oxopropanoate, 4-hydroxy-2,3-dimethyl-2H-furan-5-one,
and 3-hydroxybutan-2-one, 2-oxobutanoic acid, 2-oxopentanoic acid, ethyl pyruvate, and methyl pyruvate.
[00135] In yet other embodiments, the compound has a structure of formula (VI):
Figure imgf000035_0002
wherein:
X7, X8, and X9 are each independently selected from the group consisting of
O, S, and NH;
R13 and R14 are each independently selected from the group consisting of H,
D, a halide, and an optionally substituted aliphatic group; or R13 and R14 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
[00136] In certain embodiments, the compound has a structure of formula (Via):
33
sf-3391325 Attorney Docket No. 677032000740
Figure imgf000036_0001
wherein:
R and R are each independently selected from the group consisting of H,
OH, SH, and an optionally substituted aliphatic or he tero- aliphatic residues having 1
to 4 carbon atoms; or R13 and R14 can be linked together to form an optionally
substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
[00137] In one embodiment, the compound of formula (VI) is selected from
dimethyl carbonate, l,3-dimethyl-lH-quinazoline-2,4-dione, l,3,7-trimethyl-3,7- dihydro-purine-2,6-dione, 5,5-diethyl-pyrimidine-2,4,6-trione, 1,3-dinitro- imidazolidin-2-one, (2,5-dioxo-4-imidazolidinyl) urea, 7,9-dihydro-3H-purine-2,6,8- trione, purine-2,6-dione, l,3-dimethyl-lH-pyrimidine-2,4-dione, 6-methoxy-3H- benzooxazol-2-one, carbamic acid ethyl ester, 3H-benzothiazol-2-one, 14-nitrooxy- tetradec-5-ene, and l,2-dihydro-[l,2,4]triazol-3-one.
[00138] In yet other embodiments, the compound has a structure of formula (VII):
Figure imgf000036_0002
wherein:
X is selected from the group consisting of O, S, and NH;
R15 and R16 are each independently selected from the group consisting of H,
D, a halides, and an optionally substituted aliphatic group; or R15 and R16 can be
linked together to form an optionally substituted cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, or heterocycle.
[00139] In certain embodiments, the compound has a structure of formula (Vila):
34
sf-3391325 Attorney Docket No. 677032000740
R 1 5' " R1 6 (VIIa)
wherein:
R15 and R16 are each independently selected from the group consisting of H,
OH, SH, or an optionally substituted aliphatic or hetero- aliphatic group having 1 to 4 carbon atoms; or R15 and R16 can be linked together form an optionally substituted
aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring
carbon atoms.
[00140] In yet other embodiments, the compound has a structure of formula (VIII):
Figure imgf000037_0001
wherein;
X11 is selected from the group consisting of OH, SH, and N¾; and
R 17 , R 18 , and R 19 are each independently selected from the group consisting of
H, D, a halides, and an optionally substituted aliphatic group; or R18 and R19 and/or
R20 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
[00141] In certain embodiments, the compound has a structure of formula (Villa):
Figure imgf000037_0002
wherein:
35
sf-3391325 Attorney Docket No. 677032000740
R , R , and R are each independently selected from the group consisting of
H, OH, SH, or an optionally substituted straight or branched, saturated or unsaturated,
17 18
aliphatic or hetero-aliphatic residues having 1 to 4 carbon atoms; or two of R , R ,
and R19 can be linked together to form an optionally substituted aliphatic,
heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon
atoms.
[00142] In yet other embodiments, the compound has a structure of formula (IX):
Figure imgf000038_0001
Formula (IX)
wherein,
X -X are each independently selected from the group consisting of C, N, O, and S;
20 25
are each independently selected from the group consisting of H, D, a
halide, and an optionally substituted aliphatic group; or two or more of R20-R25 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, or heterocycle; and
20' 25'
are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or two or more of R20-R25 can
be linked together to form one or more optionally substituted cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, or heterocycle; and
20 25 20' 25'
wherein any one of R -R"J and/or R -R"J are absent if by forming a covalent bond to the corresponding X group would result in the X group exceeding the
maximum valence for that atom.
36
sf-3391325 Attorney Docket No. 677032000740
[00143] In certain embodiments, the compound has a structure of formula (IXa):
Figure imgf000039_0001
wherein:
20 22 23 25
R , R , R , and R"J are each independently selected from the group
consisting of H, D, a halides, and an optionally substituted aliphatic group; or
20 25
W" and R"J can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; and/or
R22 and R23 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
20 22 23 25
[00144] In certain embodiments of formula (IXa), R , R , R , and R are each
independently selected from the group consisting of H, OH, SH, and an optionally
substituted aliphatic or hetero-aliphatic group having 1 to 4 carbon atoms. In other
20 25
embodiments of formula (IXa), R and R can be taken together form an optionally
substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms. In yet other embodiments of formula (IXa), R22 and R23 can
be taken together form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
37
sf-3391325 Attorney Docket No. 677032000740
[00145] In certain embodiments, the compound has a structure of formula (IXb):
Figure imgf000040_0001
wherein:
R and R -R are each independently selected from the group consisting of
20
H, D, a halides, and an optionally substituted aliphatic group; or two or more of R
and R22-R25 can be linked together to form one or more optionally substituted
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
20 22 25
[00146] In certain embodiments of formula (IXb), R and R -R are each
independently selected from the group consisting of H, OH, SH, and an optionally
substituted aliphatic or heteroaliphatic groups having 1 to 4 carbon atoms. In other
20 22 25
embodiments of formula (IXb), two or more of R"" and R -R can be linked together to form an optionally substituted aliphatic or heteroaliphatic, aromatic or
heteroaromatic ring system having 4 to 6 ring carbon atoms.
[00147] In certain embodiments, the compound has a structure of formula (IXc):
Figure imgf000040_0002
wherein:
38
sf-3391325 Attorney Docket No. 677032000740
R and R -R are each independently selected from the group consisting of
H, D, a halide, and an optionally substituted aliphatic group; or two or more of R 20
and R 22 -R 25 can be linked together to form one or more optionally substituted
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
[00148] In certain embodiments of formula (IXc), R 20 and R 22 -R 25 are each
independently selected from the group consisting of H, OH, SH, and an optionally
substituted aliphatic or heteroaliphatic group having 1 to 4 carbon atoms. In other
embodiments of formula (IXc), two or more of R 2^0 and R 22 -R 2"5J can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
[00149] In certain embodiments, the compound has a structure of formula (IXd):
Figure imgf000041_0001
wherein:
R21 is selected from the group consisting of H, D, a halides, an optionally
substituted aliphatic group.
[00150] In yet other embodiments, the compound has a structure of formula (X):
Figure imgf000041_0002
39
sf-3391325 Attorney Docket No. 677032000740 wherein:
X -X are each independently selected from the group consisting of C, O, N, and S;
R26_R30
are each independently selected from the group consisting of H, D, a
halides, and an optionally substituted aliphatic group; or two or more of R26-R30 can
be linked together to form one or more optionally substituted cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, or heterocycle; and
are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or two or more R groups from
can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; and
wherein any one of R -RJU and/or R -RJU are absent if by forming a covalent bond to the corresponding X group would result in the X group exceeding the
maximum valence for that atom.
[00151] In certain embodiments, the compound has a structure of formula (Xa):
Figure imgf000042_0001
wherein;
R and R "R are each independently selected from the group consisting of
29- 30
H, D, a halides, or an optionally substituted aliphatic group; or R "R can be linked
together to form one or more optionally substituted cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, or heterocycle.
[00152] In one embodiment of formula (Xa), R and R "R are each
independently selected from the group consisting of H, OH, SH, and an optionally
substituted aliphatic or heteroaliphatic residues having 1 to 4 carbon atoms. In
40
sf-3391325 Attorney Docket No. 677032000740 another embodiment of formula (Xa), two of R "R can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring
system having 4 to 6 ring carbon atoms.
[00153] In certain embodiments, the compound has a structure of formula (Xb):
Figure imgf000043_0001
wherein:
R , and R -R are each independently selected from the group consisting of
H, D, a halides, and an optionally substituted aliphatic group; or two or more of R26,
28 30
and R -RJU can be linked together to form one or more optionally substituted
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
26 28 30
[00154] In one embodiment of formula (Xb), R and R -R are each
independently selected from the group consisting of H, OH, SH, and an optionally
substituted aliphatic or heteroaliphatic groups having 1 to 4 carbon atoms. In another embodiment of formula (Xb), two or more of R26 and R28-R30 can be linked together
to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 carbon atoms.
[00155] In certain embodiments, the compound has a structure of formula (Xc):
Figure imgf000043_0002
wherein:
41
sf-3391325 Attorney Docket No. 677032000740
R , and R -R are each independently selected from the group consisting of
26
H, D, a halide, and an optionally substituted aliphatic group; or two or more of R
28 30
and R -RJU can be linked together to form one or more optionally substituted
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
[00156] In some embodiments of formula (Xc), R , and R -R are each
independently selected from the group consisting of a halide, or an optionally
26 28 30
substituted aliphatic group. In other embodiments of formula (Xc), R , and R -R
are each other than H.
26 28 30
[00157] In one embodiment of formula (Xc), R and R -R are each
independently selected from the group consisting of H, OH, SH, and an optionally
substituted aliphatic or heteroaliphatic group having 1 to 4 carbon atoms. In another embodiment of formula (Xc), two or more of R26 and R28-R30 can be linked together
to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
[00158] In yet other embodiments, the compound has a structure of formula (XI):
Figure imgf000044_0001
wherein:
selected from the group consisting of O, S, NH, and CH2
R -R are each independently selected from the group consisting of H, D, a
halides, and an optionally substituted aliphatic group; or two or more of R31-R34 can
be linked together to form one or more optionally substituted cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, or heterocycle; and
42
sf-3391325 Attorney Docket No. 677032000740
R31'-R34' are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or two or more of R31 -R34 can
be linked together to form one or more optionally substituted cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, or heterocycle; and
wherein any one of R31-R34 and/or R31'-R34' are absent if by forming a covalent bond to the corresponding X group would result in the X group exceeding the
maximum valence for that atom.
[00159] In certain embodiments, the compound has a structure of formula (XIa):
Figure imgf000045_0001
wherein:
R31-R34 are each independently selected the group consisting of H, D, a
halides, and an optionally substituted aliphatic group; and/or two or more of R31-R34
can be linked together to form one or more optionally substituted cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
[00160] In one embodiment of formula (XIa), R31"R34 are each independently
selected from the group consisting of H, OH, SH, and an optionally substituted
aliphatic or heteroaliphatic group having 1 to 4 carbon atoms. In another embodiment of formula (XIa), two or more of R33"R36 can be linked together to form an optionally substituted aliphatic or heteroaliphatic, aromatic, heteroaromatic ring system having 4 to 6 ring carbon atoms.
[00161] In yet other embodiments, the compound has a structure of formula (XII):
43
sf-3391325 Attorney Docket No. 677032000740
Figure imgf000046_0001
wherein:
W is -NRcRd or -CRcRdRe;
Am is an aliphatic group;
each A" is independently an aliphatic group;
each Ra, Rb, Rc, Rd and Re is independently H or an aliphatic group;
each Rn is independently H or an aliphatic group; and
x is an integer greater than or equal to 1 ;
[00162] In some embodiments, W is -NRcRd.
[00163] In some embodiments, x is 0 to 8.
[00164] In certain embodiments, the compound of formula (XII) is other than
hexan-l-amine.
[00165] In some embodiments, Am is an alkyl. In some embodiments, each A" is
an alkyl. In certain embodiments, Am is a (C1-C5) alkyl. In certain embodiments,
each An is a (CI -C5) alkyl.
[00166] In one embodiment:
x is 1 or 2;
W is -NRcRd;
each Ra, Rb, Rc, Rd, and Rn is H; and
each A" and Am is independently alkyl.
[00167] In certain embodiments, the compound has a structure of formula (XIIA)
or (XIIB):
44
sf-3391325 Attorney Docket No. 677032000740
Figure imgf000047_0001
wherein each n, m and p (if present) in independent an integer greater than or equal to
1.
[00168] In certain embodiments of formula (XIIA) or (XIIB), n is 1 to 10, or 1 to 8, or 1 to 5. In one embodiment, n is 1, 2, 3, or 4.
[00169] In certain embodiments of formula (XIIA) or (XIIB), m is 1 to 10, or 1 to
8, or 1 to 5. In one embodiment, m is 1, 2, 3, or 4.
[00170] In certain embodiments of formula (XIIB), p is 1 to 10, or 1 to 8, or 1 to 5.
In one embodiment, p is 1, 2, 3, or 4.
[00171] In one embodiment, the compound is:
Figure imgf000047_0002
(spermidine).
[00172] In yet other embodiments, the compound is:
Figure imgf000047_0003
[00173] Provided herein are also compositions comprising one or more compounds of formula (I)-(XII). In some embodiments, the composition includes two or more
compounds of formula (la), (III) and (Va), or any combination thereof. In yet other
45
sf-3391325 Attorney Docket No. 677032000740 embodiments, the composition includes two or more compounds of formula (Xb) and
(XIa), or any combination thereof.
[00174] In yet other embodiments, the compound identified according to the
methods and systems described herein are selected from Table A below. Provided are also compositions including one or more, two or more, or three or more compounds
selected from Table A below.
Table A.
Figure imgf000048_0001
46
sf-3391325 Attorney Docket No. 677032000740
Figure imgf000049_0001
Formulations and Modes of Application
[00175] The compositions may further include thickeners, buffering agents,
chelating agents, preservatives, fragrances, moisturizers, antioxidants, gelling agents, stabilizers, surfactants, emollients, carriers, coloring agents, aloe vera, waxes,
lanolins, other penetration enhancers and mixtures thereof, therapeutically or
cosmetically active agents, insecticidals, or any combination thereof. In certain
embodiments, the composition may be formulated for the topical administration of the composition to the skin of a subject (e.g. , a human).
[00176] The compositions described herein may be solid-based, liquid-based, gas- based, or a mixture thereof. Liquid-based formulations may be aqueous-based or non- aqueous-based (e.g. , organic solvents), or combinations thereof, and may be
employed as lotions, ointments, foams, gels, suspensions, emulsions, microemulsions or emulsifiable concentrates or the like. The compositions may also be formulated to
be slowly released from a patch or canister.
[00177] The compositions described herein may further include one or more carrier formulation agents, including commercially-available organic and inorganic liquid
carriers, solid carriers, or semi-solid carriers or carrier formulations. Examples of
organic liquid carriers include liquid aliphatic hydrocarbons (e.g. , pentane, hexane,
47
sf-3391325 Attorney Docket No. 677032000740 heptane, nonane, decane and their analogs) and liquid aromatic hydrocarbons.
Examples of other liquid hydrocarbons include oils produced by the distillation of
coal and the distillation of various types and grades of petrochemical stocks, including kerosene oils that are obtained by fractional distillation of petroleum. Other
petroleum oils include those generally referred to as agricultural spray oils (e.g. , light and medium spray oils that include middle fractions in the distillation of petroleum
and which are only slightly volatile). Such oils are usually highly refined and may
contain only minute amounts of unsaturated compounds. Such oils, moreover, are
generally paraffin oils and accordingly can be emulsified with water and an
emulsifier, diluted to lower concentrations, and used as sprays. Tall oils, obtained
from sulfate digestion of wood pulp, like the paraffin oils, can similarly be used.
Other organic liquid carriers may include, for example, liquid terpene hydrocarbons
and terpene alcohols such as alpha-pinene, dipentene, and terpineol.
[00178] Other suitable carriers may include, for example, aliphatic and aromatic
alcohols, esters, aldehydes, ketones, mineral oil, higher alcohols, finely divided
organic and inorganic solid materials. In addition to the above-mentioned liquid
hydrocarbons, the carrier may include, for example, conventional emulsifying agents, which can be used for facilitating the dispersal of the formulation or composition to
the environment, and/or to the surface of a subject or an object. Aliphatic monohydric alcohols may include, for example, methyl, ethyl, normal-propyl, isopropyl, normal- butyl, sec-butyl, and ieri-butyl alcohols. Suitable alcohols may include, for example, glycols (e.g. , ethylene and propylene glycol) and pinacols. Suitable polyhydroxy
alcohols may include, for example, glycerol, arabitol, erythritol, and sorbitol. Suitable cyclic alcohols may include, for example, cyclopentyl and cyclohexyl alcohols.
[00179] Solid carriers that can be used in the compositions described herein may
include, for example, finely divided organic and inorganic solid materials. Suitable
finely divided solid inorganic carriers may include, for example, siliceous minerals
such as synthetic and natural clay, bentonite, attapulgite, fuller's earth, diatomaceous earth, kaolin, mica, talc, finely divided quartz, as well as synthetically prepared
siliceous materials, such as silica aerogels and precipitated and fume silicas.
Examples of finely divided solid organic materials may include cellulose, sawdust,
48
sf-3391325 Attorney Docket No. 677032000740 and synthetic organic polymers. Examples of semi-solid or colloidal carriers may
include waxy solids, gels (e.g. , petroleum jelly), and lanolin, and mixtures of liquid
and solid substances.
[00180] Additionally, the compositions or formulations described herein may
include any conventional "stabilizer" formulation agents known in the art, including, for example, ieri-butyl sulfinyl dimethyl dithiocarbonate.
[00181] The compositions described herein may include adjuvant formulation
agents used in personal care product formulations, such as thickeners, buffering
agents, chelating agents, preservatives, fragrances, antioxidants, gelling agents,
stabilizers, surfactants, emollients, coloring agents, aloe vera, waxes, lanolins, other
penetration enhancers and mixtures thereof, and therapeutically or cosmetically active agents. Therapeutically or cosmetically active formulation agents useful for the
compositions or formulations disclosed herein may include, for example,, fungicides, sunscreening agents, sunblocking agents, vitamins, tanning agents, plant extracts,
anti-inflammatory agents, anti-oxidants, radical scavenging agents, retinoids, alpha- hydroxy acids, emollients, antiseptics, antibiotics, antibacterial agents, and
antihistamines.
[00182] In some embodiments, the compositions described herein may further
include one or more insect repellent formulation agents known in the art including, for example benzil, benzyl benzoate, 2,3,4,5-bis(butyl-2-ene) tetrahydrofurfural,
butoxypolypropylene glycol, N-butylacetanilide, normal-butyl-6,6-dimethyl-5,6- dihydro- l,4-pyrone-2-carboxylate, dibutyl adipate, dibutyl phthalate, di-normal-butyl succinate, Ν,Ν-diethyl-meta-toluamide, dimethyl carbate, dimethyl phthalate, 2-ethyl- 2-butyl- 1 ,3-propanediol, 2-ethyl- 1 ,3-hexanediol, di-normal-propyl
isocinchomeronate, 2-phenylcyclohexanol, p-methane-3,8-diol, and normal-propyl
Ν,Ν-diethylsuccinamate.
[00183] The compositions described herein may include other known compatible
active formulation agents including, for example, insecticides, acaricides,
rodenticides, fungicides, bactericides, nematocides, herbicides, fertilizers, and
49
sf-3391325 Attorney Docket No. 677032000740 growth-regulating agents. In some embodiments, the agents may be in the form of
particular dosage preparations for specific application made therefrom, such as
solutions, emulsions, suspensions, powders, pastes, and granules as described herein
or as otherwise known in the art which are thus ready for use.
[00184] The compounds or compositions described herein may be administered in combination with other insect control agents. For example, the compositions may
employ various chemicals that affect insect behavior, such as insecticides, attractants and/or repellents, or as otherwise known in the art. The compounds identified by the methods and systems herein may also be administered with chemosterilants.
[00185] The amount of the compounds in the compositions described herein may
vary depending on the application. For example, in some embodiments, the
compositions described herein has at least about 0.0001 % by weight of one or more of the compounds identified by the methods or systems described herein, or about
0.0001% to about 99% by weight of one or more of the compounds identified by the
methods or systems described herein, or about 0.001 % to about 90% by weight of one or more of the compounds identified by the methods or systems described herein, or
about 0.01% to about 80% by weight of one or more of the compounds identified by
the methods or systems described herein, or about 0.1% to about 70% by weight by
weight of one or more of the compounds identified by the methods or systems
described herein, or about 1 % to about 50% by weight of one or more of the
compounds identified by the methods or systems described herein.
[00186] It should be understood that the compositions described herein contain
sufficient amounts of the one or more of the compounds identified by the methods or systems described herein so as to modulate arthropod olfactory receptors and
influence or control an arthropod' s (e.g. , insect's) behavior.
[00187] In one embodiment, the one or more of the compounds identified by the
methods or systems described herein are incorporated in effective amounts into a
composition suitable for applying to the surface of an object or subject, such as to a
subject's (e.g. , a human's) skin. Suitable compositions for topical applications
50
sf-3391325 Attorney Docket No. 677032000740 include a vehicle, such as an alcohol based solvent, a lotion such as numerous skin
creams known in the art, a silicaceous clay, or a combination thereof. One of skill in the art would recognize that, for such topical applications to be effective, the
evaporation rate of the compounds from the surface of the object or subject must be
sufficiently high enough to provide a vapor density which has the desired effect on the target arthropods. However, a balance must be struck between the evaporation rate
and the duration of the desired effect— too high of an evaporation rate will lower the
effectiveness of the arthropod olfactory receptor modulating compounds for longer
time points. Numerous extrinsic factors affect the evaporation rate, such as the
ambient temperature, the temperature of the treated surface, and the presence or
absence of air movement. Thus, it should be understood that the compositions
described herein have a surface evaporation rate of at least a minimum effective
evaporation rate. In certain embodiments, the composition has a surface evaporation rate of at least a minimum effective evaporation rate for at least 1, 2, 3, 4, 5, 6, 7, 8,
10, or 12 hours.
[00188] It should further be understood that, when formulating the compounds
described herein for specific topical applications to a subject' s (e.g. , a human's) skin, the compounds described herein are generally mixed in a dermatologically acceptable carrier, such pharmaceutically acceptable creams, polymers, lotions, gels, and/or
liquids. The pharmaceutically acceptable carriers may further provide water
repellency, prevent skin irritation, and/or soothe and condition skin. Factors to
consider when selecting a carrier(s) for any formulation with one or more compounds of the disclosure include solubility, commercial availability, cost, evaporation rate,
olfactory, stability, and whether the carrier itself exerts a biological effect on
arthropod olfactory receptors. One of skill would also recognize that the application
of the compositions and compounds of the disclosure do not only include human
subjects, but include canines, equines, bovines and other animals subject to
exoparasitic sanguinivorous feeding arthropods.
[00189] Further, it should be understood that, while the compounds identified by
the methods and systems described herein and compositions thereof are effective at
affecting arthropod olfactory receptor activity and thus arthropod behavior, under
51
sf-3391325 Attorney Docket No. 677032000740 typical conditions of use, it may under some circumstances be desirable to reduce the rate of evaporation thereof. A variety of strategies may be employed to reduce the
evaporation rate of the compounds disclosed herein, if so desired. For example, one
method is to combine the compounds disclosed herein with a polymer or other inert
ingredient, forcing the compounds disclosed herein to migrate through the mixture to the surface before it can evaporate. Alternatively, the compounds described herein
may be micro-encapsulated to control rates of evaporation from the surface of a
subject or object. In still another alternative, a precursor molecule may be prepared,
which slowly disintegrates on the surface of the subject or object thereby slowing the evaporation rate of one or more arthropod olfactory receptor modulating compounds disclosed herein to the environment. For example, release of one or more arthropod
olfactory receptor modulating compounds of the disclosure may be, for example, by
sub-micron encapsulation, in which one or more compounds disclosed herein is
encapsulated (surrounded) within a skin nourishing protein or a liposome. The protein or liposome may be used at, for example, a defined concentration. Examples of one
or more encapsulated compounds disclosed herein may include water-based lotions,
oil-based lotions, gels, or water for spray application. After coming in contact with a
subject's (e.g. , human's) skin the protein or liposomes would begin to breakdown,
thereby releasing the encapsulated arthropod olfactory receptor modulating
compounds. The process would continue as each microscopic capsule is depleted
then replaced in succession by a new capsule that contacts the skin and releases its
encapsulated arthropod olfactory receptor modulating compound. Generally, the
process may take up to 24 hours for one application. Because a protein's and
liposome' s adherence to the skin is so effective, these formulas are very resistant to
perspiration (sweat-off), and water. Alternatively, one or more arthropod olfactory
receptor modulating compounds disclosed herein may be encapsulated in polymers.
Use of such polymers, would allow for applications to slowly release one or more
arthropod olfactory receptor modulating compounds to the environment from the
surface of a subject and also from the surface of an object. Suitable polymers include, for example, high density polyethylene, low density polyethylene, biodegradable
thermoplastic polyurethanes, biodegradable ethylene polymers, and poly(epsilon
caprolactone) homopolymers and compositions containing the same, as disclosed for
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sf-3391325 Attorney Docket No. 677032000740 example in U.S. Pat. No. 4,496,467, U.S. Pat. No. 4,469,613 and U.S. Pat. No.
4,548,764. Specific examples of biodegradeable polymers include DuPont BiomaxR™ biodegradeable polyester and poly-L-lactide.
[00190] The compounds identified by the methods and systems described herein
and compositions thereof may also be applied to or impregnated onto the surfaces of an object. Examples of such applications include applying or impregnating the
compounds to clothing, netting, fabrics, bedding, screens, camping gear, leather, felt, and a sheet-like objects such as paper. Further, when applied to subjects such as pets, the compounds of the may be applied or impregnated onto resin collars.
[00191] The compounds identified by the methods and systems described herein
may also be formulated to generate solutions, suspensions, creams, ointments, gels,
films or sprays, depending on the desired method of use. The formulation agents may be aerosol-based carriers adapted to disperse the arthropod olfactory receptor
modulating compounds of the disclosure into the atmosphere by means of propellants.
Examples propellants include, for example, liquefied petroleum gas (hereinafter
referred to as "LPG") and dimethyl ether (hereinafter referred to as "DME"). One of skill in the art would recognize the desirable properties for a topical applications,
including for example low toxicity, resistance to loss by water immersion or sweating, low or no olfactory or at least a pleasant odor, ease of application, and rapid formation of a dry tack-free surface film on the subject' s (e.g. humans') skin.
[00192] In some embodiments, the compounds identified by the methods and
systems described herein may be used in products suitable for human use, including, for example, colognes, lotions, sprays, creams, gels, ointments, bath and shower gels, foam products (e.g. , shaving foams), makeup, deodorants, shampoo, hair lacquers/hair rinses, and personal soap compositions (e.g. , hand soaps and bath/shower soaps).
[00193] In other embodiments, the compounds identified by the methods and
systems described herein may be emitted from vaporizers, treated mats, cylinders,
oils, candles, wicked apparatus, and fans. For example, the compounds may be used
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sf-3391325 Attorney Docket No. 677032000740 to form vapors in barns, houses, or patios to repel insect pest and/or mask a subject
from an arthropod pest.
[00194] Certain compounds identified herein may antagonize, agonize, and/or
superagonize arthropod olfactory and/or taste receptors so as to control or influence
arthropod behavior, and/or to mask the olfactory cues of a subject or an object. Other compounds identified herein as an arthropod repellent may be used as arthropod
repellents or attractants, as masking agents for a subject or an object olfactory cues;
and/or to control and influence insect behavior, such as triggering avoidance behavior, feeding behavior, mate seeking behavior, and/or indifference to olfactory cues from a subject or an object.
[00195] The compounds and compositions described herein may be used for
inhibiting, preventing or reducing the incidence of arthropod-borne disease in a
subject, by superagonizing and/or antagonizing one or more olfactory receptors of an arthropod. In some embodiments, the receptor activity is modulated so that the
arthropod has limited to no attraction to the olfactory cues emanating from a subject, thereby inhibiting, preventing or reducing the incidence of arthropod-borne disease in a subject. In other embodiments, the arthropod-borne disease is selected from
malaria, dengue, yellow fever, river blindness, lymphatic filariasis, sleeping sickness, leishmaniasis, epidemic polyarthritis, West Nile virus disease Lyme disease, Rocky
Mountain Fever, and Australian encephalitis, or any combination thereof.
Repellent Compounds and Compositions Thereof
[00196] Provided herein are also the one or more compounds identified according
to any of the methods and systems described herein that may be used as a repellent
against at least one arthropod species.
[00197] In some embodiments, one or more of the compounds of formulae (la),
(Va), (III), and (XII), as described above, or any combinations thereof can be used as arthropod repellents. In certain embodiments, two or more of the compounds of
formulae (la), (Va), and (III), or any combination thereof, are arthropod repellents.
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[00198] Provided herein are also compositions including two or more compounds selected from compounds of formulae (IA), (VA), and (III), or any combination
thereof, for use as an arthropod repellent.
[00199] In some embodiments, the repellent composition includes:
0 one or more compounds of formula (la); and ii) one or more compounds of formulae (Va) and (III), or any combination thereof.
[00200] In certain embodiments, the repellent composition includes:
0 one or more alkyl 2-oxopropanoates; and ii) one or more compounds selected from compounds of formulae (la),
(Va) and (III), or any combination thereof.
[00201] In one embodiment, the repellent composition includes:
0 one or more compounds selected from ethyl 2-oxopropanoate and
methyl 2-oxopropanoate; and ii) one or more compounds selected from compounds of formulae (la),
(Va) and (III), or any combination thereof.
[00202] In other embodiments, one or more of the compounds of formula (XII) are arthropod repellents. Provided herein are also compositions including one or more
compounds of formula (XII) for use as an arthropod repellent.
[00203] Any combinations of the repellents disclosed herein may be used together in a blend. For example, a blend of compounds selected from compounds of formulae
(la), (Va), (III), and (XII), or any combination thereof, may be used. It should be
understood that the blend may include a compound from each formula, or multiple
compounds for a formula, or any combination thereof (e.g. , a compound from one
formula and multiple compounds from another formula). For example, the blend may
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sf-3391325 Attorney Docket No. 677032000740 include two compounds of formula (la) and a compound of formula (XII). In other
examples, the blend may include one compound of formula (la), one compound of
formula (Va), and one compound of formula (XII). In certain embodiments, the
repellent blend may include two or more compounds, three or more compounds, or
four or more compounds. In one embodiment, the repellent blend may include, two, three or four compounds of formulae (la), (Va), (III), and (XII), or any combination
thereof.
[00204] In other embodiments, the repellent compositions includes a combination
of pyruvate inhibitors and superactivators. In one embodiment, the repellent
composition includes: i) one or more pyruvate inhibitors selected from the compounds of Table A, Group II; and ii) one or more superactivators selected from the compound of Table A, Group III.
[00205] In yet other embodiments, the repellent composition includes propanal,
thiophene-2-thiol, or a combination thereof.
[00206] The arthropod repellents identified according to the methods or systems
described herein may be formulated into a repellent for topical application, such as in the form of a lotion, cream, spray or dust. In some embodiments, the repellent may be included in, for example, a vaporizer, a treated mat, treated outerwear, an oil, a
candle, or a wicked apparatus.
Attractant Compounds and Compositions Thereof
[00207] Provided herein are also the one or more compounds identified according
to any of the methods or systems described herein that may be used as an attractant
against at least one arthropod species.
[00208] In some embodiments, one or more of the compounds of formulae (la),
(Xb), (Xc), and (XIa), as described above, or any combination thereof, can be used as arthropod attractants. Provided herein are also compositions including one or more of the compounds of formulae (la), (Xb), (Xc), and (XIa), or any combination thereof,
for use as a arthropod attractant. In certain embodiments, the attractant composition
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sf-3391325 Attorney Docket No. 677032000740 includes two or more compounds of formula (la), (Xb) and (XIa), or any combination thereof. In another embodiment, the attractant composition includes two or more
compounds of formula (Xb) and (XIa), or any combination thereof.
[00209] In certain embodiments, the attractant composition includes: i) one or more compounds selected from thiophene, cyclopentanone, 1H- pyrrole, hex-5-en-2-one, methyl 2-methylpropanoate; and ii) one or more compounds selected from compounds of formulae (la),
(Xb), (Xc), and (XIa), or any combination thereof.
[00210] In certain embodiments, the attractant composition includes a
cycloalkanone, and optionally one or more compounds selected from compounds of
formulae (la), (Xb), (Xc), and (XIa), or any combination thereof. In some
embodiments, the cycloalkanone is a C4 to C6 cycloalkanone. In one embodiment, the cycloalkanone is cyclopentanone. In one embodiment, the attractant composition
includes cyclopentanone and ethyl acetate.
[00211] In other embodiments, the attractant compositions includes two or more,
three or more, or four or more compounds selected from Table A, Group I. In certain embodiments, the composition includes two, three, or four compounds selected from
Table A, Group I.
[00212] In yet other embodiments, the attractant composition includes one or more, two or more, three or more, or four or more compounds selected from 2- methylpropan-l-ol, 2-methyloxolane, 3-methylbut-3-en-l-ol, butan-2-ol, propan-2-yl formate, propan-l-ol, methyl formate, cyclopentanol, and cyclopentane. In certain
embodiments, the attractant composition includes one or more, two or more, three or more, or four or more compounds selected from 2-methyloxolane, propan-2-yl
formate, methyl formate, cyclopentanol, and cyclopentane.
[00213] The arthropod attractants identified according to the methods or systems
described herein may be used to lure an arthropod into a trap. For example, the trap
may be suction-based, light-based, electric current-based.
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EXAMPLES
[00214] The following examples are merely illustrative and are not meant to limit any embodiments of the present disclosure in any way.
Example 1
Ability of cpA receptor neuron to detect human skin odorants
[00215] This Example demonstrates that volatiles from human skin may directly
activate cpA. In particular, human foot odor collected directly onto glass beads is
sufficient to activate the cpA neuron in A. aegypti.
Materials and Methods
[00216] Electrophysiology: Adult female A. aegypti (Linnaeus 1762) (Rockefeller strain) A. gambiae sensu stricto Giles 1902 (G3 strain), or C. quinquefasciatus Say
1823 were tested 3-12 days post-emergence with single-sensillum extracellular
recordings. Chemicals were obtained from Sigma- Aldrich at the highest purity
(typically >99 ) and were dissolved in paraffin oil or water. Human odor was
collected on glass beads worn in socks for ~6hrs and 20 ml beads were placed inside a
25 ml disposable pipette through which a puff of air was delivered, switching from a comparable cartridge containing clean beads (FIG. 7a). Response to clean beads was subtracted from the results reported. Only sensilla with cpA activity of <20 spikes s"1 to negative control were considered for analysis.
[00217] CpA-off and sham treated mosquitoes were pre-treated for 3 min in an
upended 1L glass dish in which 100 μΐ of fresh butyryl chloride (1%) or paraffin oil
was allowed to vaporize for 10-20 min. The odor delivery system for different
screens is shown in FIG. 7b; solvent responses during the same recording session
were subtracted. Inhibition screen was tested. For the ultra-prolonged activator the 3-s stimulus was delivered from a 10 ml disposable pipette using a CS-55 stimulus
controller (Syntech), C02 was delivered, and responses to subsequent odor stimuli
were calculated by subtracting baseline activity 1 s prior to each stimulus. When
responses to repeated pulses of cyclopentanone and C02 were compared, baseline
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sf-3391325 Attorney Docket No. 677032000740 activity between seconds 5 and 6 following each stimulus was subtracted. Spike
counting was done manually or with Igor Pro6.2 (Wavemetrics) with the Neuromatic v2.00 macro (by Jason Rothman), and peak-to-peak spike amplitudes for FIG.8 were analysed in Clampfit 10.3 (Molecular Devices).
Results
[00218] A panel of odorants selected from the hundreds of compounds that were
detected in human skin, sweat, or associated microbial odors for structural similarity
to known ligands of cpA (Table 1 below).
Table 1. Panel of odorants
Figure imgf000061_0001
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Figure imgf000062_0001
[00219] The panel of odorants were tested for activity with single-sensillum
electrophysiology. Over 35% of these odorants activated the neuron strongly (>30
spikes s"1) in A. aegypti (FIG. lc). The neuron's responses to these skin-derived
odorants were observed to be comparable to its response to C02 (FIG. Id, FIG. 9a)
and are dose-dependent (FIG. le).
[00220] Although the anthropophilic A. aegypti and A. gambiae belong to
divergent mosquito subfamilies separated by 145-200 million years of evolution, their
C02 receptor genes are highly conserved. Based on the data in this Example, the
responses of the cpA neuron to this panel of odorants were found to be similar
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sf-3391325 Attorney Docket No. 677032000740 between these two species (FIG. lc), suggesting a conserved role in detecting host
odor.
Example 2
Involvement of cpA neuron for attraction to human skin odor
[00221] This Example demonstrates the involvement of cpA activation by human
odor for attraction, using a novel chemical-based strategy to shut down the activity of the C02 receptor in A. aegypti.
Materials and Methods
[00222] Electroantennogram analysis: Standard whole-antenna recordings were
performed with minor modifications. Traces were averaged using Clampfit software
(Molecular Devices), and responses were normalized to interspersed pulses of a
reference odorant, 3-methyl-l-butanol, according to the formula: Raw response
(mV)/(«x + by), where a and b are the responses (mV) to the immediately previous
and subsequent reference odor stimulation, respectively, and x and y are the
proportion of time elapsed between stimuli (so that x + y = \). Response to reference
odorant did not significantly differ across treatment groups.
[00223] Wind tunnel: Room air (27°C; 35^40% relative humidity was carbon
filtered and drawn through a glass wind tunnel (36 cm x 40 cm x 128 cm) in a laminar flow at a constant rate of 0.2 m s"1. Beads were elevated 7 cm above the floor of the
wind tunnel in a covered 10 cm-diameter petri dish, 50 cm upwind from the release
cage (Fig. 2h). Female A. aegypti were held in individual release cages without access to food or water for 17-23 hr at -27° C and -70% relative humidity and pre-exposed to fresh butyryl chloride (1%) or solvent as above. The mosquito rested in the release cage for at least 60 s, following which covers over the beads and the release cage exit were removed to start the assay, video-recorded for 5 min. Landing was defined as
alighting or walking onto the bead surface. Trials were conducted between 1400 and
1830 h. Days with poor response in positive control were not considered.
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[00224] Short-range attraction: Ten 6-day-old female A. aegypti were starved 30
hrs in a 7 cm diameter x ~5 cm high cage with wire mesh on one side and placed
inside an aquarium. After 5 min a beaker with 750 ml warm water (40° C) and filter
paper soaked with 400 μΐ water were placed 5 mm above the cage (FIG. 9e). CpA-off and sham treated mosquitoes were video-recorded and counted at 30 s intervals.
Results
[00225] Butyryl chloride is a reactive volatile compound and is structurally related to two of the strongest known inhibitors of the C02 receptor, butyraldehyde and
butanoic acid (FIG. 2a). A single puff of 1% butyryl chloride inhibits cpA from firing in response to subsequent C02 stimuli. Based on dose-response and time -response
experiments, a 3-min exposure to a small quantity (100 1, 10"2) of butyryl chloride
volatiles in an upended glass dish was determined to completely abolished cpA's
subsequent responses to 1% C02 (FIGS. 2b and 2c) or exhaled breath (not shown)
when tested in a period -5-20 min after exposure. The neuron's responses to
activating skin odorants were also substantially reduced after this pre-exposure (FIGS.
2b and 2c). The inhibition of cpA was observed to be long-lasting and recovered to
control levels between 12-24 hours after treatment (FIG. 9b).
[00226] The observed effect is specific to the cpA neuron of the palp. Odor-evoked responses of the other two neurons in the same sensillum (cpB and cpC), which
express members of the Or gene family, were not reduced after the treatment (FIG.
2d). In fact, these neurons showed a slight increase in activity. The summed response of antennal neurons to foot odor, with or without butyryl chloride treatment, was not statistically different in electroantennogram (EAG) recordings (FIGS. 2e and 2f).
Likewise, the summed responses of antennal neurons to a panel of skin odorants,
including those that have been previously implicated in host-seeking behaviour, was
also unaffected by butyryl chloride treatment (FIG. 9c and FIG. 9d).
[00227] Moreover, the response of cpA to foot odor collected on beads was also
completely lost when tested -5-20 min after exposure (FIG. 2g). The ability to
specifically shut down cpA responses provides a system to test whether the neuron is
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sf-3391325 Attorney Docket No. 677032000740 involved in attraction towards human skin odor. A. aegypti females were observed to initiate upwind flight, navigate upwind, and land on a dish of foot-odor beads
presented in a wind tunnel even in the absence of a C02 plume (FIGS. 2h-2k). The
proportion of mosquitoes that landed on the human odor beads was substantially
reduced after pre-exposure to butyryl chloride (FIG. 2i). Analysis of flight videos
indicated that the proportion of cpA-off mosquitoes that initiated upwind flight from
the release cage was greatly reduced and indistinguishable from the proportion of
control mosquitoes that initiated upwind flight in the absence of any human odor
(FIG. 2j).
[00228] Most sham-treated control mosquitoes took off relatively quickly towards foot odor, but the cpA-off mosquitoes that did take off did so throughout the five- minute period of the assay (FIG. 10). CpA-off mosquitoes that did take off from the
release cage showed no deficit in ability to fly (FIG. 10). Of these, less than half
successfully navigated to or landed on the beads; the behaviour of others resembled
that of no-odor controls (FIG. 2k, FIG. 10). Residual landing behaviour observed in
treated mosquitoes may be mediated by short-range cues that are detected by other
olfactory neurons or due to incomplete shutdown of the cpA neuron in tested
individuals. In a separate control assay, pre-exposure to butyryl chloride did not
impair mosquitoes' ability or preference for resting at the top of a small cage, or the
increase in this preference when a warm, moist stimulus was introduced above the
cage (FIG. 9e and FIG. 9f), which suggests that general physical or behavioural
deficits are unlikely. Taken together, these results show that the highly conserved C02 receptor-containing neuron detects human skin odorants and mediates attraction
towards skin odor.
Example 3
In silico identification of cpA activators and inhibitors for human use
[00229] In this Example, ligands that have stronger effects on cpA activity are
identified using an in silico screen. Such ligands are pleasant smelling, safe, and
affordable. Using cheminformatics, structural features shared amongst known ligands
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(inhibitors and activators) of the CC>2-sensitive neuron were identified and a structure comparison approach was used to identify new ligands from an extremely large
chemical space (>440,000, including 3,197 volatiles from natural sources) (FIG. 3a).
[00230] Existing data on odor-evoked activity for the cpA neuron that expresses
the conserved C02 receptor from A. aegypti, A. gambiae, and Culex quinquefasciatus as well as Drosophila melanogaster was compiled to generate training sets for
cheminformatic analysis. Known ligands fell into multiple structural classes,
suggesting the possibility of distinct binding pockets on the receptor. In order to
improve chances of identifying structural features for these potentially distinct
binding sites, active compounds were separated into three training sets:
aromatic/cyclic ligands, straight-chain ligands, and ligands from both sets together.
[00231] A single energy-minimized 3D structure was obtained for each odor in the training set and the values for 3,224 molecular descriptors from Dragon (Talete) were calculated. A small subset of molecular descriptors whose values were highly
correlated with electrophysiological activity was selected through application of a
Sequential Forward Selection method. This process was applied independently for
each of the training sets, resulting in three separate activity-optimized molecular
descriptor sets (Tables 2a, 2b and 2c below). 3D and 2D molecular descriptors were
preferentially selected, suggesting that shape-related features were important for
interaction with the receptor.
Table 2a. Aromatic/cyclic optimized descriptors
Figure imgf000066_0001
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Table 2b. Combined-ligands optimized descriptors
Figure imgf000067_0001
Table 2c. Aliphatic optimized descriptors
Figure imgf000067_0002
[00232] The library of >440,000 chemicals by their computationally determined
similarity to known ligands using the three optimized descriptor sets and generated
three lists of predicted ligands that cumulatively represent numerous potential ligands for the C02 receptor-expressing cpA neuron.
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Example 4
Predicted ligands contain effective activators, inhibitors, and an ultra-prolonged
activator
[00233] From the large list of cpA receptor ligands predicted from Example 3
above, 138 compounds were selected based on desirable criteria for application such
as smell, presence in natural sources, human safety profile, and cost to procure. These compounds were tested individually using single- sensillum electrophysiology on the
cp sensillum of female A. aegypti, according to the procedure described in Example 1 above.
[00234] Approximately 30% of the tested odors activated the cpA neuron with >30 spikes s"1 (FIG. 3b). To our satisfaction, -85% of these activators are already
approved for use as flavor, fragrance, or cosmetic agents and many have been listed in
"generally recognized as safe" (GRAS) list by the Flavor and Extract Manufacturer's
Association (Table 3 below).
Table 3. List of tested odors
Figure imgf000068_0001
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Figure imgf000069_0001
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Figure imgf000070_0001
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Figure imgf000071_0001
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Figure imgf000072_0001
*n/d refers to "no data"
[00235] Several of these were also pleasant-smelling to humans. Odorants in this
initial electrophysiology screen were presented in a manner so that cpA's background firing rate was raised during stimulation by -50 spikes s 1, thus also revealing a
number of potential inhibitors (FIG. 3b).
[00236] Along with the 15 odors that reduced the background firing rate, all
odorants that did not activate cpA with >40 spikes s"1 were retested in an additional
electrophysiology screen for ability to inhibit response to an overlaid 0.15% C02
stimulus (FIG. 3c). Several compounds inhibited cpA to some degree; ethyl pyruvate strongly inhibited cpA activity (FIG. 3c and Table 3 above). A structurally related
odorant, methyl pyruvate, also strongly inhibited cpA even at low concentrations
(FIG. 3c, Table 3 above, FIG. 11a). Comparable inhibition was observed at -10 times lower concentrations than for previously reported inhibitors such as 1-hexanol.
[00237] Additionally, longer-term recordings with newly-discovered activators
revealed that a 3-s exposure to (E)-2-methylbut-2-enal results in sustained firing of
cpA at -45 spikes s"1 for at least 5.5 min (FIG. 3d,e). Responses to 1-s pulses of
0.15% C02 during this period are significantly reduced relative to controls (FIG. 3f), suggesting that this odor, which smells better (green fruit) than butanedione (rancid
butter), may also disrupt navigation towards a C02 source.
Example 5
A cpA inhibitor reduces attraction of mosquitoes to skin
[00238] This Example demonstrates that an inhibitory odorant may block attraction of mosquitoes to skin.
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Materials and Methods
[00239] Hand-in-cage: Forty 4-10-day-old female A.aegypti were starved 24 hrs
and released in a 30 x 30 cm cage with a glass top, and trials commenced between
1400 and 1700 hrs. A human hand wearing a nitrile glove (Sol-vex) with a 7 x 6 cm
window covered by two layers of fine polyester mesh (BioQuip, mesh size 26 x 22
holes per in2) held in place by magnetic spacers, was inserted into the cage. The
lower mesh was 1.5 mm above, and upper mesh was 6 mm above the hand. While
skin emanations passed freely through the mesh window, the hand was protected from contact with mosquitoes and treated mesh. The outside mesh was treated with ethyl
pyruvate (500μ1, 10% in acetone) or solvent. After letting solvent evaporate the glove was assembled. Experimenter inserted a hand in a control glove into the cage for 5
min, then the same hand was placed inside a test glove and reinserted into the same
cage for an additional 5min. Trials were video recorded and mosquitoes on the mesh
were counted every 15 s.
Results
[00240] The cpA inhibitor ethyl pyruvate was selected for testing since it is listed
as a GRAS compound, is approved as a flavor agent in food, and has a pleasant smell
(fruity, sweet, rum, caramel) (Table 3 above). Ethyl pyruvate completely eliminates
response of the cpA neuron to human foot odor when they are presented together
(FIG. 4b).
[00241] An arm-in-cage repellency assay was used in this Example using gloves
with chemical treated mesh-covered windows to quantify attraction of A. aegypti
mosquitoes to the human hand without exposing the hand to mosquito bites or skin to contact with test chemicals. Ethyl pyruvate substantially reduced the number of times mosquitoes landed on the mesh over a human hand (FIG. 4c). The simplest
interpretation of these results when considered along with the previous wind tunnel
experiments is that inhibition of the cpA neuron reduces attraction by masking
detection of skin odor.
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Example 6
A cpA activator lures mosquitoes to a trap as effectively as C02
[00242] This Example demonstrates whether an odorant that can mimic C02- mediated activation of the cpA neuron can substitute for C02 as an effective lure.
Materials and Methods
[00243] Semi-field trapping: Two modified greenhouses at the Agricultural
Experiment Station at the University of California, Riverside, were used as described previously2, with modifications. Fifty laboratory-reared, mated, non-blood fed female
C. quinquefasciatus aged 8-14 days and starved for 24 hrs were released each evening around 5pm and traps collected at ~7am. Counter flow geometry traps baited with
C02 (250 ml min-1, -670 mmol/hr) odorant were used as described2, with
modifications. Odorant solutions in water were dispensed from 20 cm long gauze
wicks protruding from uncapped 50 ml tubes beneath the trap outflow. For each trial, one baited trap and one control trap (water-filled) were placed in each of two
greenhouses (Fig. 4g). For two-choice C02 trials, water was placed under both traps.
For two-choice ethyl pyruvate trials, both traps expelled C02, and one trap also
released ethyl pyruvate from an open 2.8 x 7 cm glass vial. Since ethyl pyruvate has
very low volatility pure compound was used to generate -1.7 mmol/hr. An empty vial was placed under control traps. Treatment position and trap were alternated across
trials. Volume of solution lost from tubes containing 5%, 10%, or 20%
cyclopentanone were measured after each trial and the average loss of molecules
calculated respectively for 3 concentrations as (±s.d.) of 0.7 (±0.1), 1.7 (±0.4), and
3.8 (±0.3) mmol/hr, respectively. Preference index = (# mosquitoes in odor-baited
trap - # mosquitoes in control trap)/( total # mosquitoes caught in both traps).
Results
[00244] Dose response curves were generated for two strong activators in both A.
aegypti and C. quinquefasciatus (FIG. 4d, FIG. l ib). Cyclopentanone is a strong
activator in both these species, is approved as a flavor and fragrance agent, is listed as
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sf-3391325 Attorney Docket No. 677032000740 a GRAS substance, and also has a pleasant minty smell (Table 3 above).
Cyclopentanone mimics C02's temporal activation profile to repeated 1-s stimuli
(FIG. 4e,f), and the cpA neuron tracks changes in levels of both compounds with
similar temporal acuity (FIG. 4e, FIG. 11c), suggesting that mosquitoes will be able to efficiently navigate along plumes of this odorant. Taken together, the strong and
conserved cpA response, promising safety and fragrance profile, and ability to mimic
C02 activation made cyclopentanone an excellent candidate for behavioural testing.
[00245] The efficacy of cyclopentanone as a lure was tested using traps in
controlled semi-field experiments with C. quinquefasciatus, a mosquito present in
Southern California, where the experiments took place. 50 female mosquitoes were
released overnight in a modified greenhouse that contained two counter-flow
geometry mosquito traps (FIG. 4g). One trap was baited with an evaporative lure of
cyclopentanone diluted in water, and the second trap was baited with water alone.
Mosquitoes preferred cyclopentanone over solvent-baited traps in a dose-dependent
manner (FIGS. 4h and 4i). Remarkably, capture numbers for traps baited with
cyclopentanone were comparable to those recorded for traps baited with C02 in
similar trials performed in parallel (FIGS. 4h and 4i). The number of molecules of
cyclopentanone released, calculated from the amount that evaporated during the
assay, was ~176-fold less than the number of molecules of C02 released to produce a comparable catch rate (Online Methods). To our knowledge, no other odorant-based
lure has been able to trap mosquitoes effectively in the absence of C02, let alone at
rates comparable with C02. For example, traps baited with 10% lactic acid, one of the few known weak attractants of mosquitoes in laboratory assays, did not catch
significantly more mosquitoes than control traps (FIG. 4i).
[00246] The same assay was also used to test whether the inhibitor ethyl pyruvate
could mask detection of a C02 source. A C02-baited trap that was also dispensing
ethyl pyruvate caught significantly fewer mosquitoes than a control C02-baited trap
(FIG. 4i).
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sf-3391325 Attorney Docket No. 677032000740
Example 7
Odor space detected by the cpA neuron
[00247] This Example explores the nature of the odorant chemical space detected
by the cpA neuron.
Materials and Methods
[00248] Optimized descriptor sets: A single energy-minimized 3D structure was
generated for each chemical using Omega2 software (OpenEye). 3,224 molecular
descriptors were calculated from 3D structures with the Dragon software package
(Talete), values were normalized across compounds, and descriptors that did not show variation were removed. Optimized descriptor subsets were iteratively identified using a Sequential Forward Selection (SFS) method. The SFS approach selected descriptors that increased the correlation between ligand activity and chemical similarity,
calculated using Euclidean distance from descriptor values. Ligands that evoked >30 spikes s"1 were classified as activators, and those that reduced baseline firing rate by
>5 spikes s"1 were classified as inhibitors. This process was run independently for
each of 3 training sets (aromatic/cyclic ligands, straight-chain ligands, and a
combined set), resulting in 3 unique descriptor subsets. These three activity-optimized descriptor subsets were combined into a single descriptor set with 64 descriptors
representing molecular features that predict C02 receptor activity. Optimized
descriptor values were used to cluster active ligands and as features for principle
component analysis (PCA). Computational analysis was performed in R.
[00249] Ligand prediction: Each activity-optimized descriptor set was applied to
rank a library of >440,000 compounds based on the Euclidean distance of each
chemical from a previously known ligand. The compound library comprised 3,197
51 52 20—23 53—
volatile compounds from known origins including plants , insects , humans
55 , a fragrance collection56 including fruit and floral volatiles, and additional
compounds from the eMolecules catalogue selected for having similar physical
properties to known odorants (< 350 MW and atoms C, O, N, H, I, CI, S, F).
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sf-3391325 Attorney Docket No. 677032000740
[00250] Ligand prediction using SVM: A new receptor-optimized descriptor set
(Table 4) was calculated based on ligand activity data for A. aegypti alone (this
study). This descriptor set was utilized to train a Support Vector Machine (SVM)
using regression and a radial basis function kernel available in the R package el071, which integrates libsvm. Optimal gamma and cost values were determined using the
Tune. SVM function. The resulting trained SVM was then applied to predict activity
for compounds from the >440,000 compounds.
[00251] Computational Validation: Twenty independent 5-fold cross-validations of the computational approach was performed. For each validation, the dataset of known ligands was randomly divided into 5 equal sized partitions and 4 of the partitions were applied to train the SVM and the remaining partition, which was not used for training, was used to test predictive ability. This process was repeated 5 times for each
independent run with each partition excluded and used to test predictive ability
exactly once. The overall predictive ability was calculated as a single receiver
operating characteristic (ROC) curve for all 20 independent validations.
[00252] Selection of compounds for screening: Predicted ligands were screened for organoleptic odor profile using a flavor and fragrance database. Compounds that did not have foul smells and were categorized as flavor, fragrance or cosmetic agents
were considered for purchase. A few additional compounds were also selected after
cross-checking MSDSs and other literature to leave out carcinogens, neurotoxins, etc.
Results
[00253] The action potentials evoked in the cp sensillum by C02, whole foot odor, and odorants from multiple structural classes were first analyzed to confirm that
cpA's action potentials can be distinguished unambiguously in each case by their
characteristically large relative spike amplitude (FIG. 8). To investigate structural
similarities of cpA ligands, their relationships in chemical space were analyzed. The 3 sets of optimized descriptors used to predict cpA ligands (FIG. 3a) include a total of
64 molecular descriptors representing structural features that predict cpA activity, so
were used to map the position of each tested skin odorant in 64-dimensional space.
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sf-3391325 Attorney Docket No. 677032000740
Principle component analysis (PCA) makes it possible to visualize the optimized
descriptor-based relationships between each of the tested skin odorants in a 3- dimensional chemical space (dark green dots, FIG. 5a). Most active skin odorants
were observed to be present in a relatively small region of this chemical space.
Ligands that were predicted in silico and confirmed as activators by electrophysiology
(light green dots, FIG. 5a) populate regions that overlap with the active skin odorants.
Inhibitory odorants also overlap the same regions, suggesting that their effect may be mediated via similar binding sites on the C02 receptor (red dots, Fig 5a). Odorants
that did not show activity are mostly found in a non-overlapping region (grey dots,
FIG. 5a).
[00254] Next, this Example seeks to determine whether an additional set of 110
compounds that had previously been tested on an A. gambiae odor receptor (Or)
repertoire, including many skin odorants, occupied a similar region of chemical space.
Although these diverse compounds are broadly dispersed, they show limited overlap
with the cpA ligand space (black dots, FIG. 5a). The functional groups were observed to distributed widely in optimized-descriptor defined chemical space (FIG. 5b). By
superimposing activity of the cpA ligands using bubble plots as before, it becomes
apparent that stronger ligands include chemicals from diverse functional classes (FIG.
5c). Presumably relevant parts of 3D chemical structure are more important in
bringing these ligands together in chemical space than characteristics like functional group.
[00255] Hierarchical clustering was used to group ligands of the C02 receptor by
structural similarity, measured by Euclidean distance in 64D optimized descriptor
space (FIG. 5c). The resulting tree had roughly three branches, each populated by
structurally distinct odor classes: substituted pyrazines and pyridines, other cyclic
compounds, and short aliphatic chemicals. These three broad ligand classes and C02 appear structurally different, and it will be interesting to test whether they bind to
different regions of the heteromeric C02 receptor (Grl, Gr2, and Gr3).
[00256] Additionally, predictionary accuracy was increased through machine
learning. The activities of the newly tested odorants (FIGS, lc, 3b, and 3c) allowed
76
sf-3391325 Attorney Docket No. 677032000740 for further improved ligand predictions for the C02 receptor. The activities of all
tested odorants were used to identify a single optimized descriptor set as before
(Table 4 below).
Table 4. Optimized descriptor set
Figure imgf000079_0001
[00257] A machine learning approach called Support Vector Machine (SVM) was incorporated to select C02 receptor ligands. A widely applied computational
validation called 5-fold cross validation indicated that the SVM based approach had a substantially higher Area-under-curve (AUC) value indicating improved ligand
prediction (FIG. 5e). From the top 200 ligand predictions made using this method, 20 compounds were obtained and tested, of which 13 activated the cpA neuron >30
spikes"1, and 2 inhibited the neuron, yielding a remarkably improved success rate of
75% (FIG. 5f, Table 5 below).
77
sf-3391325 Attorney Docket No. 677032000740
Table 5.
Figure imgf000080_0001
Example 8
Amines for use as repellents
[00258] This example demonstrates that certain polyamine compounds may exhibit repellent activity. The amines listed in Table 6 below were tested using an assay to
determine inhibition of C02 receptor neuron activity.
78
sf-3391325 Attorney Docket No. 677032000740
Table 6.
Figure imgf000081_0001
[00259] Dose response values for spermidine and spermine were also determined, as sumarized in Table 7 below. The polyamines were diluted 0.001 to 10% in paraffin oil (PO). Also shown in Table 7 are the activity values of the C02 receptor neuron
during the spermidine and spermine stimulus windows (error bars=s.e.m.).
Table 7.
Boss- esji ns* 3er*s- ¾ liillll -
S 3 S.B s.a
32,3 Ώ. 4.S -1.S i.3 S.a
5-5.5 * -j <G s 3.4
3ρ 0' ¾¾, {¾"<=■§}: ■ma 13.3 S 7 85. ί S 9.S & 1
5.3 «5.4 Si.2 !4.S 5 1
S ίϊΐ=ΰ S.0 4.8 S-ί ΐ
5 .S 11.3 "5.5 S3 0 0 as
52.Ώ ■iO.S . : -δ «2 2.5
52. J § 3 3.7 -3.2 W:i 4.4
SpswsiKS: 3 Ί % = 'iSJ 14. -3 4.5 73,5 22Λ 7.Ξ
2.7 2.7 > ΐ Sf.S ss 2 4
23 85. ΐ S.3 S 4
79
sf-3391325

Claims

Attorney Docket No. 677032000740
What is claimed is:
1. A method for identifying a compound that is a repellent for at least one
arthropod species, comprising: a) providing a candidate compound and a skin odor; b) providing a sample comprising a neuron, wherein the neuron expresses at least one of Grl, Gr2, and Gr3 or any orthologs thereof; c) contacting the candidate compound with the sample; d) measuring the detection of the skin odor by the neuron; e) comparing the detection of the skin odor by the neuron after contact
with the candidate compound to the detection of the skin odor by the neuron in the
absence of the candidate compound; and f) identifying a compound that is a repellent for at least one arthropod
species by determining whether or not the candidate compound masks or inhibits the detection of the skin odor by the neuron.
2. The method of claim 1 , wherein the skin odor is an individual odorant, or the
skin odor comprises a plurality of odorants.
3. The method of claim 1 or 2, wherein the neuron is a cpA neuron.
4. The method of any one of claims 1 to 3, wherein the compound that is a
repellent for at least one arthropod species is identified by determining whether or not the candidate compound masks or inhibits at least 75% of the detection of the skin
odor by the neuron.
5. The method of any one of claims 1 to 4, wherein the activity of the neuron is
measured by one or more electrophysiological parameters, one or more activity
imaging parameters, or any combinations thereof.
80
sf-3391325 Attorney Docket No. 677032000740
6. A system, comprising: a) a sample comprising a neuron, wherein the neuron expresses at least
one of Grl, Gr2, and Gr3, or any orthologs thereof; b) a skin odor; and c) one or more compounds that each is a repellent for at least one
arthropod species, wherein the one or more compounds each masks or inhibits the
detection of the skin odor by the neuron during or after exposure to the one or more
compounds.
7. The system of claim 6, wherein the skin odor is an individual odorant or the
skin odor comprises a plurality of odors.
8. The system of claim 6 or 7, wherein the neuron is a cpA neuron.
9. The system of any one of claims 6 to 8, wherein the one or more compounds
each masks or inhibits at least 75% of the detection of the skin odor by the neuron.
10. A composition for use as an arthropod repellent, comprising two or more
compounds selected from the compounds of formulae (la), (Va) and (III):
Figure imgf000083_0001
wherein:
R1 and R2 are each independently selected from the group consisting H, OH,
SH, and an optionally substituted aliphatic or hetero-aliphatic group having 1 to 6
carbon atoms; or R1 and R2 can be linked together to form an optionally substituted
aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 3 to 6 ring
carbon atoms,
81
sf-3391325 Attorney Docket No. 677032000740
Figure imgf000084_0001
wherein:
R11 and R12 are each independently selected from the group consisting of H,
OH, SH, and an optionally substituted aliphatic or he tero- aliphatic group having 1 to
4 carbon atoms; or R11 and R12 can be linked together to form an optionally
substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms,
Figure imgf000084_0002
wherein:
R5 and R6 are each independently selected from the group consisting of H, D, a halide, and optionally substituted aliphatic group; and
R7 is selected from the group consisting of an optionally substituted aliphatic
group; or
R5 and R6 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; or
R6 and R7 can be linked together to form an optionally substituted ring
selected from the group consisting of cycloalkenyl, aryl, and heterocycle, or any combinations thereof.
82
sf-3391325 Attorney Docket No. 677032000740
11. The composition of claim 10, wherein the one or more compounds of formula
(la) are one or more alkyl 2-oxopropanoates.
12. A composition for use an arthropod repellent, comprising one or more
compounds of formula (XII):
Figure imgf000085_0001
wherein:
W is -NRcRd;
Am is an aliphatic group;
each A" is independently an aliphatic group;
each Ra, Rb, Rc and Rd is independently H or an aliphatic group;
each Rn is independently H or an aliphatic group; and
x is an integer greater than or equal to 1 ;
13. The composition of claim 12, wherein:
x is 1 or 2;
W is -NRcRd;
each Ra, Rb, Rc, Rd, and Rn is H; and
each A" and Am is independently alkyl.
14. The composition of claim 12, wherein the compound is:
Figure imgf000085_0002
A composition for use as an arthropod repellent, comprising
83
sf-3391325 Attorney Docket No. 677032000740 i) one or more pyruvate inhibitors selected from the compounds of Table A,
Group II; and ii) one or more super activators selected from the compound of Table A,
Group III.
16. A composition for use as an athropod repellant, comprising propanal,
thiophene-2-thiol, or a combination or mixture thereof.
17. The composition of any one of claims 10 to 16, wherein composition is
formulated into a lotion, a cream, a spray, a dust, a vaporizer, a treated mat, a treated
outerwear, an oil, a candle, or a wicked apparatus.
18. A composition for use as an arthropod attractant, comprising two or more of
the compounds of formulae (la), (Xb), (Xc), and (XIa):
Figure imgf000086_0001
wherein:
R1 and R2 are each independently selected from the group consisting H, OH,
SH, an optionally substituted aliphatic or hetero- aliphatic group having 1 to 6 carbon atoms; or R1 and R2 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 3 to 6 ring carbon
atoms,
Figure imgf000086_0002
wherein:
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sf-3391325 Attorney Docket No. 677032000740
R , and R -R are each independently selected from the group consisting of
H, D, a halides, and an optionally substituted aliphatic group; or two or more of R26, and R 28 -R 3J0U can be linked together to form one or more optionally substituted
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle,
Figure imgf000087_0001
wherein:
R 26 , and R 28 -R 3J0U are each independently selected from the group consisting of
H, D, a halides, and an optionally substituted aliphatic group; or two or more of R26
and R28-R30 can be linked together to form one or more optionally substituted
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle,
Figure imgf000087_0002
wherein:
R31-R34 are each independently selected the group consisting of H, D, a
halides, and an optionally substituted aliphatic group; and/or two or more of R31-R
can be linked together to form one or more optionally substituted cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, or heterocycle, or any combination thereof.
19. A composition for use as an arthropod attractant, comprising:
85
sf-3391325 Attorney Docket No. 677032000740 i) one or more compounds selected from thiophene, cyclopentanone, 1H- pyrrole, hex-5-en-2-one, methyl 2-methylpropanoate; and ii) one or more compounds selected from compounds of formulae (la),
(Xb), (Xc), and (XIa), or any combination thereof.
20. A composition for use as an arthropod attractant, comprising: i) a cycloalkanone; and ii) optionally one or more compounds selected from compounds of
formulae (la), (Xb), (Xc), and (XIa), or any combination thereof
21. A composition for use as an arthropod attractant, comprising 2-methylpropan- l-ol, 2-methyloxolane, 3-methylbut-3-en-l-ol, butan-2-ol, propan-2-yl formate,
propan-l-ol, methyl formate, cyclopentanol, cyclopentane, or any combinations or
mixtures thereof.
86
sf-3391325
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